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Good afternoon, everybody.

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We are going to go ahead and start.

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People are still kind of trickling in.

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Apologies for the food being late,

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but it usually makes
people happy to have food,

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so we like to be able to
set the stage with that.

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So it is my pleasure to
be here this afternoon

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to introduce our university
scholar presentation.

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We are 42 years into University Scholars

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at the graduate college,

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and this is our third
speaker of four for the year,

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and, obviously, you're
welcome to get refreshments

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and you can get them and go back out there

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if you need to during the talk or not.

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We don't mind if you do that.

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So the purpose of the
University Scholar Award

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is to recognize excellence

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and, basically, history and longevity

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and really doing fabulous research

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in creative works and scholarship.

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So, today, in that vein,

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we recognize Professor Anne Dixon,

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Somewhere over my vision there,

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who is, I have to read these,

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the interim chair of medicine,

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the director of the Division of Pulmonary

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and Critical Care of Medicine,

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the director of the Vermont Lung Center,

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and a professor of medicine.

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Dr. Dixon is originally from England

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and moved to the United States

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after completing her undergraduate studies

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at Cambridge University

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and Medical School at Oxford University.

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She completed residency
training in internal medicine

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at Johns Hopkins in Baltimore,

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and a pulmonary and
critical care fellowship

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at the University of Washington

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before joining the faculty at UVM in 2001.

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Her research career is focused

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on clinical and translational studies

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to understand mechanisms
linking obesity and asthma,

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and she has led basic translational

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and clinical trials on this topic.

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Dr. Dixon has over 100 publications

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and has led a number of
international workshops

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and symposia.

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She was the editor of
the first book published

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on obesity and lung disease,

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and is currently working on the
second edition of that book.

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She has been recognized for this work

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with an American Thoracic
Society Achievement Award

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and honored by the Asthma and
Allergy Foundation of America

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New England chapter

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with a Champion Award
for her contributions.

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In addition to her research contributions,

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she recently served on the expert panel

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updating the national asthma guidelines

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for the National Heart and
Lung and Blood Institute.

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She also chairs the
Scientific Advisory Committee

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for the American Lung Association

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and the American Board
of Internal Medicine

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Pulmonary Board
Certification Exam Committee.

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There's a lot more we could
tell you about Dr. Dixon,

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but we always like to stop

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and just share something light

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about our University
Scholars presentations,

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and for Dr. Dixon, as we've
learned from a colleague,

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that she rode for Oxford University

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during her days as a medical student

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and I mean rode, like, boats, not horses.

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-(crowd laughing)
-Very impressive.

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And with that,

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I'm pleased to now
introduce Professor Dixon

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for her inaugural University
Scholars lecture entitled

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"Fat and Flow:

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Elucidating the link
Between Obesity and Asthma",

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and she'll take questions at
the conclusion of the talk.

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(crowd applauding)

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Well, thank you, Dean Forehand,

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for that very lovely introduction

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and thank you, all of
you, for being here today.

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This means a lot.

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It really does.

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And so, what I thought
I would start off with

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was talking a little
bit about my background,

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because, I think, when you
hear it from Dean Forehand,

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it all sounds very straightforward

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and I know for the young
people sitting in the audience,

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it sort of sounds like,

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"Whoa, she really knew
what she was doing,"

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and that might not be the exact truth.

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I'll explain to you how
I got to my interest

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in obesity and asthma,

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and then I'll tell you about

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the research that we've done

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to try and elucidate the
pathogenesis of this disease,

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and a lot of work we've tried to do here

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on how to treat this disease,

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and a lot of people who
actually do the work

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are sitting here in the audience,

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so thank you for coming.

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So I'm originally from a town

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in the southwest of
England called Plymouth.

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It's an area which is a
beautiful part of the country,

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has lots of dairy farms
and lots of tourists.

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Sounds familiar, doesn't it?

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One of my early memories, actually,

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is of my grandfather
happened to auction off

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the animals and the
equipment from his farm.

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He had really bad farmers' lung disease,

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which probably is one of the reasons

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I ended up in pulmonary medicine.

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I was lucky enough to go to
two very beautiful places

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where I did a little bit of work

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and a lot of rowing actually.

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That's something I usually
try and hide from people,

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but it was a glorious time.

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And after internship, I did something

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to my mother's horror, actually,

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I married an American.

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-(crowd laughing)
-And so, it wasn't like

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I was on a trajectory

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to go from Oxford to Hopkins
by any manner of means,

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but I married an American,

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and so, the deal was,

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if I moved to the United States,

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the moves thereafter would be mine,

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which is important to
make that sort of deal.

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So he was actually finishing up law school

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in Ann Arbor, Michigan,

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and so, I ended up in Ann Arbor

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for nearly a couple of years,

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doing exams, including
the English language test

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and also worked in a lab looking
at retinoic acid receptors.

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But then I got my exams,

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we found a place where
both of us could work,

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and so, we moved to the
Baltimore-Washington area

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where I did residency at Hopkins,

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which was a wonderful place to work,

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and I still have friends
and colleagues from Hopkins

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that I work with today.

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But, you know, for a girl from Plymouth,

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the Baltimore-Washington
area is not necessarily

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where you wanna spend your entire life.

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And all the moves were mine, right?

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And so, we moved to Seattle, Washington,

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which was a fabulous pulmonary
and critical care division.

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I actually worked in a lab

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at the Fred Hutchinson
Cancer Research Center

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for my research,

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looking at post bone marrow
transplant lung injury,

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the same lab as Dr. Dan Weiss.

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The two of us have been
together for a long time.

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(audience member speaking faintly)

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(Dr. Dixon laughing)

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And that research was
going really, really well,

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but I kind of got to my fourth year.

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I got a great score on an NRSA,

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but, you know, I had a
two and a half year old,

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I was pregnant, and I was like,

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"How does anyone do academic medicine

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and take care of their family?"

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And so, I did a complete 180.

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My poor husband's getting
whiplash by this stage,

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but we moved back to the east coast,

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because that's where the family is

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and we ended up in Chapel
Hill, North Carolina.

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I actually took a job in private practice.

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Well, I lasted two weeks

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before realizing that was the
biggest mistake of my life.

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I was doing outpatient pulmonary

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and it was great lifestyle-wise,

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but I really, really
missed academic medicine,

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and so, I called back to my
mentors in Seattle who said,

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"Well, Polly Parsons has
just moved to Vermont

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and she is hiring so you
should give her a call."

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So after about a year,

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I ended up here at the
University of Vermont

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and I have loved my time here.

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But I was originally hired
as a clinical scholar,

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so pretty much as a clinician.

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But I was really lucky,

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and I was lucky,

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because Charlie Irvin and David Kaminsky,

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at that time had just started working

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with the American Lung Association

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Airway Clinical Research Centers,

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and this has really been a very
important part of my career.

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I think there were 19 centers
at that time, right, Charlie?

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We were the only one in New England

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and I started working with them,

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and I was working on a project
on sinus disease and asthma,

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and, actually, I got my K23
doing sinus disease and asthma.

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When there was a study

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that Charlie was actually the PI on

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that had a really unusual finding.

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This was a study where,

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if we treated people with
Theophylline to improve asthma

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and there were three
really important findings

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that really caught my interest.

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One of which was over 50% of
our participants were obese,

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so a really high prevalence
of obesity at a time

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when in the nation, it
was about 30% of the time.

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People with obesity tended

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to have much worse asthma control.

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And when we put them on Theophylline,

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we made them even worse.

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So, if you were skinny and
we put you on Theophylline,

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you had fewer exacerbations,

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whereas if you were obese and
we put you on Theophylline,

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you got worse, and this
really sparked my interest.

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We still haven't entirely figured out

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the reason you get worse on Theophylline,

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but more of that later.

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This was, I think, the
second paper that came out

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that suggested altered responses

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to medications in people with asthma

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and there've been a whole bunch since.

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So I thought, "Well,

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obesity seems to be making asthma worse.

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Where do you go from
here to figure it out?"

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Well, we work in a really,
really collaborative place.

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And so, I went to my
bariatric surgeon colleagues

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and a big thank you to them.

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Dr. Forgione and Dr. Abarjaz
have put up with me for years,

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and we did a study in
bariatric surgery asking,

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does weight loss improve asthma control?

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A really simple question.

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Patients lost a lot of weight,

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so their BMI went from,
on average, 51 down to 37,

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their asthma control improved
very, very significantly.

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So the asthma control score here

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before surgery was 1.55.

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1.5 or above is considered
poorly controlled asthma.

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0.75 or below is considered
well controlled asthma.

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So, they went on average,

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from having very poorly controlled asthma

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to well-controlled asthma.

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Their FEV1/FVC,

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the ways we measure lung
function, also improved,

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so things were looking at a lot better.

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But one of the ways that we
really try and figure out

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what is going on with asthma,

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asthma, the airways are
inflamed, they're twitching,

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and so, we wanted to see

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whether, how reactive the
airways, if that changed.

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And that was kind of a more nuanced story.

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Because we found that some patients,

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their airway reactivity really improved.

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And the way that you look at this graph,

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we measure airway reactivity.

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Oh, I completely lost the pointer.

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So on the Y-axis is looking

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at the concentration of
methacholine required

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to produce a 20% fall
in your lung function,

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so the lower you are on the Y-axis,

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the twitchier are your airways,

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and so, there was a group of people

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who had non-allergic asthma

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who went from having very twitchy airways

262
00:10:38,280 --> 00:10:39,843
to getting much better.

263
00:10:41,040 --> 00:10:42,330
But there was another group,

264
00:10:42,330 --> 00:10:45,270
people with early-onset allergic asthma

265
00:10:45,270 --> 00:10:46,620
who, their airway reactivity

266
00:10:46,620 --> 00:10:48,810
did not seem to change much at all,

267
00:10:48,810 --> 00:10:50,430
suggesting for the first time

268
00:10:50,430 --> 00:10:51,450
that there was at least

269
00:10:51,450 --> 00:10:54,900
two phenotypes of asthma
in people with obesity.

270
00:10:54,900 --> 00:10:56,190
Now this is sort of, you know,

271
00:10:56,190 --> 00:10:57,780
I'm showing this complicated graph.

272
00:10:57,780 --> 00:11:01,680
Really, a couple of patients
really brought home to me

273
00:11:01,680 --> 00:11:03,960
what these two phenotypes were.

274
00:11:03,960 --> 00:11:05,280
Because, in this non-allergic,

275
00:11:05,280 --> 00:11:09,930
there was a woman who developed
asthma in her late thirties

276
00:11:09,930 --> 00:11:12,600
the year before she
underwent bariatric surgery.

277
00:11:12,600 --> 00:11:14,730
She was in the ICU six times,

278
00:11:14,730 --> 00:11:17,310
six times with asthma exacerbations.

279
00:11:17,310 --> 00:11:20,190
She went through bariatric
surgery, she lost weight,

280
00:11:20,190 --> 00:11:22,470
she got off all asthma medications,

281
00:11:22,470 --> 00:11:26,010
so really transformed her asthma.

282
00:11:26,010 --> 00:11:27,660
And in the allergic group,

283
00:11:27,660 --> 00:11:30,660
there was a woman I ran
into at the coffee thing

284
00:11:30,660 --> 00:11:32,460
on the second floor over there one day

285
00:11:32,460 --> 00:11:35,220
and I said, "How are
you doing these days?"

286
00:11:35,220 --> 00:11:36,810
And she said, "Well,
you know what Dr. Dixon?

287
00:11:36,810 --> 00:11:37,800
I feel much better.

288
00:11:37,800 --> 00:11:39,270
I can walk up the stairs.

289
00:11:39,270 --> 00:11:41,160
I don't wheeze, I don't cough,

290
00:11:41,160 --> 00:11:44,190
but every time I go to my
daughter's house with the cat,

291
00:11:44,190 --> 00:11:45,870
I get wheezy again."

292
00:11:45,870 --> 00:11:48,780
And so, this really threw
it into sharp relief

293
00:11:48,780 --> 00:11:51,630
what these two phenotypes of asthma were.

294
00:11:51,630 --> 00:11:54,570
And so, we described these
two different phenotypes

295
00:11:54,570 --> 00:11:58,620
and I like to think of them as
asthma consequent to obesity,

296
00:11:58,620 --> 00:12:01,563
and asthma complicated by obesity,

297
00:12:02,490 --> 00:12:04,680
and more, both of these.

298
00:12:04,680 --> 00:12:05,940
So, the first thing,

299
00:12:05,940 --> 00:12:09,777
we'd identified this form of
late onset non-allergic asthma

300
00:12:09,777 --> 00:12:11,730
and the obvious question is,

301
00:12:11,730 --> 00:12:14,100
why on Earth are these
people developing asthma?

302
00:12:14,100 --> 00:12:15,303
What is going on?

303
00:12:16,890 --> 00:12:18,900
Now for those of you that
don't think about asthma,

304
00:12:18,900 --> 00:12:20,520
I can't imagine why you wouldn't,

305
00:12:20,520 --> 00:12:24,840
but asthma is an inflammatory
disease of of the airway.

306
00:12:24,840 --> 00:12:25,680
So, on your left,

307
00:12:25,680 --> 00:12:28,140
you see a nice, wide open airway,

308
00:12:28,140 --> 00:12:29,460
and on your right,

309
00:12:29,460 --> 00:12:32,190
what you see is a mucus filled, narrowed,

310
00:12:32,190 --> 00:12:34,170
and planed airway,

311
00:12:34,170 --> 00:12:37,290
and this is driven by certain cytokines,

312
00:12:37,290 --> 00:12:39,090
what we call the Type 2 cytokines,

313
00:12:39,090 --> 00:12:42,150
IL-4, IL-5, IL-13,

314
00:12:42,150 --> 00:12:44,580
increased mucus production,

315
00:12:44,580 --> 00:12:45,720
gunk in the airways,

316
00:12:45,720 --> 00:12:47,703
eosinophilic mass cells.

317
00:12:48,780 --> 00:12:51,090
So asthma is an inflammatory disease.

318
00:12:51,090 --> 00:12:51,923
Well, you know what?

319
00:12:51,923 --> 00:12:53,826
Obesity is an inflammatory disease, right?

320
00:12:53,826 --> 00:12:55,410
We know that.

321
00:12:55,410 --> 00:12:57,450
And so, this is a photo micrograph

322
00:12:57,450 --> 00:12:59,640
that was for a patient

323
00:12:59,640 --> 00:13:03,060
before and 12 months
after bariatric surgery.

324
00:13:03,060 --> 00:13:05,670
And the photo micrograph
there on the left,

325
00:13:05,670 --> 00:13:07,290
the blue is nucleus staining,

326
00:13:07,290 --> 00:13:10,320
the red is CD68 staining for macrophages,

327
00:13:10,320 --> 00:13:13,890
and what you can see is, that
before bariatric surgery,

328
00:13:13,890 --> 00:13:16,200
or at the time of bariatric surgery,

329
00:13:16,200 --> 00:13:18,630
this adipose tissue is infiltrated

330
00:13:18,630 --> 00:13:20,670
with these pro-inflammatory macrophages

331
00:13:20,670 --> 00:13:22,500
that throw out high levels of cytokines

332
00:13:22,500 --> 00:13:25,020
such as IL-6 TNF-alpha.

333
00:13:25,020 --> 00:13:29,400
12 months later, in the same
patient, it's less cellular.

334
00:13:29,400 --> 00:13:33,120
The adipose sites themselves
are actually smaller.

335
00:13:33,120 --> 00:13:36,480
So, fat in the setting of obesity

336
00:13:36,480 --> 00:13:39,930
is a much more pro-inflammatory tissue.

337
00:13:39,930 --> 00:13:41,880
And so, I came up with what seems like

338
00:13:41,880 --> 00:13:44,160
the obvious hypothesis, right?

339
00:13:44,160 --> 00:13:46,230
So asthma is an inflammatory disease.

340
00:13:46,230 --> 00:13:47,340
So my hypothesis was

341
00:13:47,340 --> 00:13:50,340
that inflammation associated with obesity

342
00:13:50,340 --> 00:13:52,233
increases airway inflammation.

343
00:13:53,910 --> 00:13:55,290
So we did the experiment,

344
00:13:55,290 --> 00:13:56,490
and what we had done was,

345
00:13:56,490 --> 00:13:59,010
we'd done bronchoalveolar lavage

346
00:13:59,010 --> 00:14:01,620
on these patients at the
time of bariatric surgery,

347
00:14:01,620 --> 00:14:02,550
and on the left panel,

348
00:14:02,550 --> 00:14:05,520
what you're looking at here is,

349
00:14:05,520 --> 00:14:09,060
on the gray is controls at
the time of bariatric surgery,

350
00:14:09,060 --> 00:14:11,070
the dark gray is asthmatics

351
00:14:11,070 --> 00:14:12,990
at the time of bariatric surgery,

352
00:14:12,990 --> 00:14:16,620
and the black is the
asthmatics 12 months later.

353
00:14:16,620 --> 00:14:18,420
And what you can see from a bunch of these

354
00:14:18,420 --> 00:14:22,980
inflammatory cytokines, IL-8, NCP, TNF,

355
00:14:22,980 --> 00:14:25,590
they actually increase after weight loss,

356
00:14:25,590 --> 00:14:28,800
so completely opposite my hypothesis.

357
00:14:28,800 --> 00:14:30,480
and the other thing that we did

358
00:14:30,480 --> 00:14:33,450
was we took out lymphocytes
and peripheral blood,

359
00:14:33,450 --> 00:14:36,480
so we took out CD4 positive lymphocytes

360
00:14:36,480 --> 00:14:40,470
and we just stimulated them
in vitro with CD3 and CD28,

361
00:14:40,470 --> 00:14:42,970
and the panel on the
left shows a composite

362
00:14:44,130 --> 00:14:45,930
from controls at time zero,

363
00:14:45,930 --> 00:14:48,060
asthmatics before bariatric surgery,

364
00:14:48,060 --> 00:14:51,840
and then asthmatics 12 months
after bariatric surgery,

365
00:14:51,840 --> 00:14:53,070
and lo and behold,

366
00:14:53,070 --> 00:14:54,600
you stimulate the lymphocytes

367
00:14:54,600 --> 00:14:57,180
of patients 12 months
after bariatric surgery,

368
00:14:57,180 --> 00:15:00,390
and they produce much higher
levels of these cytokines.

369
00:15:00,390 --> 00:15:02,793
So completely opposite of what I thought.

370
00:15:04,500 --> 00:15:06,440
Matt Poynter and Jen Ather
have actually shown this

371
00:15:06,440 --> 00:15:07,860
in a much more elegant way

372
00:15:07,860 --> 00:15:10,020
in a house dust mite mouse model

373
00:15:10,020 --> 00:15:12,390
where they used low fat, lean mice,

374
00:15:12,390 --> 00:15:14,880
high fat, obese mice,

375
00:15:14,880 --> 00:15:18,153
and mice that were switched
from high fat to a low fat diet.

376
00:15:19,080 --> 00:15:20,070
And what they did was,

377
00:15:20,070 --> 00:15:21,990
they took the spleens out of these mice,

378
00:15:21,990 --> 00:15:24,510
much easier to do in mice
than to do in humans,

379
00:15:24,510 --> 00:15:27,000
and they stimulated it
with house dust mite

380
00:15:27,000 --> 00:15:28,110
and what you can see is

381
00:15:28,110 --> 00:15:31,740
the high fat diet mice
produced much lower levels

382
00:15:31,740 --> 00:15:33,330
of the cytokines that they measured,

383
00:15:33,330 --> 00:15:37,770
including IL-5, IL-13, and IL-17.

384
00:15:37,770 --> 00:15:40,473
So, quite contrary to my hypothesis.

385
00:15:42,210 --> 00:15:45,240
Obesity was not increasing
allergic inflammation

386
00:15:45,240 --> 00:15:47,103
by any manner of means.

387
00:15:48,000 --> 00:15:50,280
But what was also really interesting

388
00:15:50,280 --> 00:15:53,160
was when we looked at the adipose tissue

389
00:15:53,160 --> 00:15:57,900
of these asthmatics,
compared to obese controls,

390
00:15:57,900 --> 00:16:00,630
the adipose tissue, the
visceral adipose tissue

391
00:16:00,630 --> 00:16:03,690
of obese asthmatics is more inflammatory.

392
00:16:03,690 --> 00:16:06,060
It produces higher levels of leptin,

393
00:16:06,060 --> 00:16:08,220
it's got more macrophages,

394
00:16:08,220 --> 00:16:10,800
and it's got lower levels
of things like adiponectin

395
00:16:10,800 --> 00:16:13,680
which has anti-inflammatory effects.

396
00:16:13,680 --> 00:16:17,100
So we are seeing inflammatory
disease in the adipose tissue,

397
00:16:17,100 --> 00:16:18,390
but not the airway.

398
00:16:18,390 --> 00:16:19,800
And, actually, when we looked

399
00:16:19,800 --> 00:16:22,290
at visceral fat leptin
expression, you can see,

400
00:16:22,290 --> 00:16:25,903
the more leptin you get,
the twitchier your airways.

401
00:16:25,903 --> 00:16:27,390
I don't know if that's causation,

402
00:16:27,390 --> 00:16:30,030
but that's pretty interesting.

403
00:16:30,030 --> 00:16:31,830
And this is since been supported

404
00:16:31,830 --> 00:16:33,960
by numerous other publications.

405
00:16:33,960 --> 00:16:38,130
A group in Australia did
a very similar study to us

406
00:16:38,130 --> 00:16:39,930
and a group out at UCSF

407
00:16:39,930 --> 00:16:44,160
has done a lot of works
showing circulating IL-6,

408
00:16:44,160 --> 00:16:47,640
which is produced predominantly
by adipose tissue,

409
00:16:47,640 --> 00:16:49,680
is associated with poor asthma control

410
00:16:49,680 --> 00:16:52,320
and increased asthma exacerbations.

411
00:16:52,320 --> 00:16:55,350
Based on that, they're doing
a a study of anti-IL-6.

412
00:16:55,350 --> 00:16:57,360
I personally think the IL-6

413
00:16:57,360 --> 00:17:00,720
is just a mark of metabolic dysfunction.

414
00:17:00,720 --> 00:17:04,440
So, what is the adipose tissue doing?

415
00:17:04,440 --> 00:17:06,870
Well, Matt Poynter has done a lot of work

416
00:17:06,870 --> 00:17:08,940
trying to sort this out.

417
00:17:08,940 --> 00:17:12,210
And he found, when he
takes conditioned medium

418
00:17:12,210 --> 00:17:13,770
from adipose tissue

419
00:17:13,770 --> 00:17:18,150
and puts that on antex mouse
airway epithelial cells,

420
00:17:18,150 --> 00:17:22,470
it modulates cytokine production
perhaps not surprisingly.

421
00:17:22,470 --> 00:17:24,450
The other really interesting
thing in this paper

422
00:17:24,450 --> 00:17:26,820
that they published back
in '21 is, actually,

423
00:17:26,820 --> 00:17:30,570
the mouse epithelial cells from obese mice

424
00:17:30,570 --> 00:17:32,610
produce different levels of cytokines

425
00:17:32,610 --> 00:17:37,050
than the epithelial
cells from the lean mice.

426
00:17:37,050 --> 00:17:39,720
So it's not just that the
adipose tissue has changed,

427
00:17:39,720 --> 00:17:42,150
but the airway cells
themselves have changed

428
00:17:42,150 --> 00:17:43,563
in the setting of obesity.

429
00:17:44,730 --> 00:17:47,070
So a lot of work still to
sort of figure that out,

430
00:17:47,070 --> 00:17:50,340
but at the same time we were
really trying to understand,

431
00:17:50,340 --> 00:17:51,450
to inform treatment,

432
00:17:51,450 --> 00:17:54,180
what are the physiologic
functional characteristics

433
00:17:54,180 --> 00:17:57,333
of this late onset non-allergic asthma.

434
00:17:58,290 --> 00:17:59,970
Because how are we gonna
figure out how to treat it

435
00:17:59,970 --> 00:18:00,933
if we don't know?

436
00:18:02,190 --> 00:18:04,680
Well, we had done a study way, way back

437
00:18:04,680 --> 00:18:07,260
where we had looked at lung elastance,

438
00:18:07,260 --> 00:18:11,250
you know lung stiffness before
and after bariatric surgery,

439
00:18:11,250 --> 00:18:13,230
and the white here is obese controls

440
00:18:13,230 --> 00:18:14,670
before bariatric surgery.

441
00:18:14,670 --> 00:18:17,010
The light-gray is obese controls

442
00:18:17,010 --> 00:18:19,293
12 months after bariatric surgery.

443
00:18:20,160 --> 00:18:21,930
The middle-gray, I guess I'll call it,

444
00:18:21,930 --> 00:18:24,270
is asthmatics before bariatric surgery,

445
00:18:24,270 --> 00:18:27,000
and the really dark gray is
asthmatics post weight loss.

446
00:18:27,000 --> 00:18:30,180
And what you can see
is that the asthmatics

447
00:18:30,180 --> 00:18:32,850
have really high lung elastance,

448
00:18:32,850 --> 00:18:34,560
compared to the obese control

449
00:18:34,560 --> 00:18:36,633
and that's when controlled for weight.

450
00:18:38,310 --> 00:18:40,890
We since just had another study

451
00:18:40,890 --> 00:18:42,840
that's been accepted for publication

452
00:18:42,840 --> 00:18:45,270
where we found that this
is a little more nuanced.

453
00:18:45,270 --> 00:18:49,530
And so, we looked at
response to our Methacholine

454
00:18:49,530 --> 00:18:53,220
in our obese controls,
and our obese asthmatics.

455
00:18:53,220 --> 00:18:56,340
And we were able to identify

456
00:18:56,340 --> 00:18:58,950
there is a subgroup of
these obese asthmatics

457
00:18:58,950 --> 00:19:01,020
when we give them Methacholine,

458
00:19:01,020 --> 00:19:02,670
and we look at their lung reactants.

459
00:19:02,670 --> 00:19:05,490
Their lung reactants is measured by airway

460
00:19:05,490 --> 00:19:06,930
under the curve of the reactants,

461
00:19:06,930 --> 00:19:09,810
goes to really, really high levels.

462
00:19:09,810 --> 00:19:11,790
They have really, really stiff lungs

463
00:19:11,790 --> 00:19:13,830
when you give them Methacholine.

464
00:19:13,830 --> 00:19:15,660
There's a group of obese asthmatics

465
00:19:15,660 --> 00:19:18,663
that don't look that
different than obese controls.

466
00:19:20,070 --> 00:19:21,630
And, actually, when we went back

467
00:19:21,630 --> 00:19:23,080
and we looked at their lungs

468
00:19:24,420 --> 00:19:26,040
before we gave them Methacholine,

469
00:19:26,040 --> 00:19:28,890
you could even then pick out this group

470
00:19:28,890 --> 00:19:31,260
that have got stiff lungs at baseline,

471
00:19:31,260 --> 00:19:34,320
which just gets worse with Methacholine.

472
00:19:34,320 --> 00:19:36,510
Well, so what?

473
00:19:36,510 --> 00:19:37,650
Well, there's a couple of things

474
00:19:37,650 --> 00:19:39,420
that are really interesting about this,

475
00:19:39,420 --> 00:19:41,640
is, one, you cannot detect,

476
00:19:41,640 --> 00:19:43,680
which this subgroup is

477
00:19:43,680 --> 00:19:45,780
by doing conventional lung function test.

478
00:19:45,780 --> 00:19:48,727
You have to use a technique
that we call oscillometry.

479
00:19:49,890 --> 00:19:53,190
So there is a group here with
developing really stiff lungs

480
00:19:53,190 --> 00:19:55,080
and these really stiff lungs

481
00:19:55,080 --> 00:19:58,950
are associated with increased
symptoms of chest tightness,

482
00:19:58,950 --> 00:20:01,200
increased wheeze,

483
00:20:01,200 --> 00:20:04,890
and in this group, they also
had more asthma exacerbations

484
00:20:04,890 --> 00:20:09,120
in the 12 months before we studied them.

485
00:20:09,120 --> 00:20:10,920
So there is a group of people

486
00:20:10,920 --> 00:20:13,710
who are coming to us complaining
of a lot of symptoms.

487
00:20:13,710 --> 00:20:14,543
They're wheezing,

488
00:20:14,543 --> 00:20:15,630
they've got chest tightness,

489
00:20:15,630 --> 00:20:17,880
they're getting lots of exacerbations,

490
00:20:17,880 --> 00:20:20,100
their lung periphery is
really, really stiff,

491
00:20:20,100 --> 00:20:21,960
and we have got no good
way of detecting it

492
00:20:21,960 --> 00:20:24,727
unless we do this technique
called oscillometry.

493
00:20:26,730 --> 00:20:28,713
But what is causing this?

494
00:20:30,150 --> 00:20:33,090
And so, it looks like the
periphery of their lung

495
00:20:33,090 --> 00:20:34,690
is getting really, really stiff.

496
00:20:35,940 --> 00:20:38,340
And so, we had this obvious hypothesis,

497
00:20:38,340 --> 00:20:40,490
is that their airways
were collapsing down.

498
00:20:41,970 --> 00:20:44,040
And so, we recruit four groups,

499
00:20:44,040 --> 00:20:48,120
we recruited lean controls and asthmatics

500
00:20:48,120 --> 00:20:50,250
and obese controls and asthmatics,

501
00:20:50,250 --> 00:20:51,963
and we did an imaging study

502
00:20:51,963 --> 00:20:54,270
with our help from radiology here,

503
00:20:54,270 --> 00:20:56,513
Brian Walsh, and a very talented postdoc

504
00:20:56,513 --> 00:20:58,740
who was working with us at the time,

505
00:20:58,740 --> 00:21:00,000
and we did CTs.

506
00:21:00,000 --> 00:21:03,810
This is an obese control at
the top on full inhalation,

507
00:21:03,810 --> 00:21:06,270
and what you can see here is
the left main stem bronchus,

508
00:21:06,270 --> 00:21:08,070
right main stem bronchus,

509
00:21:08,070 --> 00:21:10,980
beautiful black lungs during inhalation,

510
00:21:10,980 --> 00:21:12,870
you breathe all the way out

511
00:21:12,870 --> 00:21:15,060
and the airways completely disappear.

512
00:21:15,060 --> 00:21:16,710
This is not normal.

513
00:21:16,710 --> 00:21:19,860
So the airways are not supposed
to completely collapse down

514
00:21:19,860 --> 00:21:21,120
and this is an obese control.

515
00:21:21,120 --> 00:21:23,430
There's nothing wrong with this patient.

516
00:21:23,430 --> 00:21:25,590
If you look at an obese asthmatic,

517
00:21:25,590 --> 00:21:28,800
beautifully patent left and
right lane stand bronchus,

518
00:21:28,800 --> 00:21:29,910
black lungs,

519
00:21:29,910 --> 00:21:32,580
they exhale the airways disappear

520
00:21:32,580 --> 00:21:34,530
just like the obese controls do,

521
00:21:34,530 --> 00:21:36,300
but you also get the sense

522
00:21:36,300 --> 00:21:37,950
that their lungs are a little blacker,

523
00:21:37,950 --> 00:21:41,460
and so, we published that
this tendency of the airways

524
00:21:41,460 --> 00:21:44,100
to collapse, this Tracheobronchomalacia ,

525
00:21:44,100 --> 00:21:45,330
or as it's called now,

526
00:21:45,330 --> 00:21:47,850
expiratory dynamic airway collapse,

527
00:21:47,850 --> 00:21:49,650
seems to be related to BMI,

528
00:21:49,650 --> 00:21:51,360
it's not related to obesity

529
00:21:51,360 --> 00:21:52,620
and I think it's likely leading

530
00:21:52,620 --> 00:21:56,520
to an epidemic of Tracheiobronchomalacia.

531
00:21:56,520 --> 00:22:00,000
But it's not explaining our asthma.

532
00:22:00,000 --> 00:22:01,380
But what is happening is,

533
00:22:01,380 --> 00:22:03,510
when we look at the
characteristics of the lung,

534
00:22:03,510 --> 00:22:06,120
so this is whiteness of the lung,

535
00:22:06,120 --> 00:22:08,220
which is sort of complete collapse

536
00:22:08,220 --> 00:22:10,560
measured by high attenuation area

537
00:22:10,560 --> 00:22:12,780
versus blackness of the lung,

538
00:22:12,780 --> 00:22:15,060
which is air trapping,

539
00:22:15,060 --> 00:22:17,370
and you see the obese controls,

540
00:22:17,370 --> 00:22:19,230
compared to this LONA group,

541
00:22:19,230 --> 00:22:21,240
their lungs are not as white

542
00:22:21,240 --> 00:22:24,450
and they're blacker, so
they've got more air trapping,

543
00:22:24,450 --> 00:22:27,180
and age was a really
important co- variant of this.

544
00:22:27,180 --> 00:22:30,510
And another postdoc working
with Jason Bates and myself,

545
00:22:30,510 --> 00:22:35,510
Swati Batwa was the first
author on this study.

546
00:22:35,700 --> 00:22:37,980
And this, I think, is one of the reasons

547
00:22:37,980 --> 00:22:41,340
we're seeing this as patients get older,

548
00:22:41,340 --> 00:22:44,343
why age is an important
co-variant, we don't know.

549
00:22:45,990 --> 00:22:48,630
And so, what's causing this tendency?

550
00:22:48,630 --> 00:22:51,960
They're developing this air
trapping, we don't know.

551
00:22:51,960 --> 00:22:52,950
A lot of different theories,

552
00:22:52,950 --> 00:22:54,990
some of them we're trying to work on

553
00:22:54,990 --> 00:22:56,700
is it increased smooth muscle tone?

554
00:22:56,700 --> 00:22:58,890
Is it increased airway liquid?

555
00:22:58,890 --> 00:23:01,320
Is it abnormal surfactant function?

556
00:23:01,320 --> 00:23:02,793
Watch this space.

557
00:23:03,810 --> 00:23:05,400
So though we don't know what's causing it,

558
00:23:05,400 --> 00:23:07,350
I'm a clinician, I'm very pragmatic.

559
00:23:07,350 --> 00:23:10,920
I do think this tells us how
we might be able to treat it.

560
00:23:10,920 --> 00:23:12,300
So, if they're collapsing down,

561
00:23:12,300 --> 00:23:14,190
one way that we might be able to treat it

562
00:23:14,190 --> 00:23:16,533
is by giving positive airway pressure.

563
00:23:17,610 --> 00:23:22,610
And so, we recently published
a study with Jason Bates

564
00:23:24,960 --> 00:23:26,610
in which we gave Methalcholine

565
00:23:26,610 --> 00:23:29,370
to some of these late onset
nonallergic asthmatics,

566
00:23:29,370 --> 00:23:32,790
and we measure the development
of elastance in black

567
00:23:32,790 --> 00:23:35,190
with no positive expiratory pressure

568
00:23:35,190 --> 00:23:38,070
and in red sort of with this
positive expiratory pressure,

569
00:23:38,070 --> 00:23:40,530
so it gives you a little bit
of breath assist if you like

570
00:23:40,530 --> 00:23:41,700
when you breathe out.

571
00:23:41,700 --> 00:23:45,060
And you can see the
elastances don't get as high

572
00:23:45,060 --> 00:23:46,470
in these obese asthmatics,

573
00:23:46,470 --> 00:23:50,310
and, actually, this correlates
with lower respiratory rate,

574
00:23:50,310 --> 00:23:51,960
and increased tidal volume,

575
00:23:51,960 --> 00:23:54,660
suggesting that positive
expiratory pressure

576
00:23:54,660 --> 00:23:58,200
may be a great intervention
for these folks.

577
00:23:58,200 --> 00:24:01,050
And so, we're actually just
completing a study right now,

578
00:24:01,050 --> 00:24:02,370
looking at the efficacy

579
00:24:02,370 --> 00:24:04,680
of continuous positive airway pressure

580
00:24:04,680 --> 00:24:07,170
for these folks giving it at night.

581
00:24:07,170 --> 00:24:08,610
That seemed like a great idea.

582
00:24:08,610 --> 00:24:10,890
Anybody hates sleeping with CPAP though?

583
00:24:10,890 --> 00:24:12,840
So maybe not,

584
00:24:12,840 --> 00:24:15,480
but another thing that we
have just started working on

585
00:24:15,480 --> 00:24:19,560
is giving us CPAP with exercise.

586
00:24:19,560 --> 00:24:22,440
So these people we think
are developing air trapping

587
00:24:22,440 --> 00:24:23,670
and it's really difficult.

588
00:24:23,670 --> 00:24:24,750
They are not gonna show you,

589
00:24:24,750 --> 00:24:26,910
they don't recruit the lung very well.

590
00:24:26,910 --> 00:24:29,220
And so, if you're over at
the Fanny Island one day

591
00:24:29,220 --> 00:24:30,780
and you see a bunch of people walking

592
00:24:30,780 --> 00:24:33,420
up and down the hallway
with CPAP machines on,

593
00:24:33,420 --> 00:24:34,840
they are part of our study.

594
00:24:34,840 --> 00:24:37,890
(audience giggling)

595
00:24:37,890 --> 00:24:41,460
So that's this late onset
non-allergic asthma of obesity.

596
00:24:41,460 --> 00:24:45,000
What about early-onset allergic asthma?

597
00:24:45,000 --> 00:24:49,260
Because it's really much
complicated by obesity.

598
00:24:49,260 --> 00:24:52,140
This is not the same as lean disease.

599
00:24:52,140 --> 00:24:56,280
And for clinicians out there,
if you look at these people,

600
00:24:56,280 --> 00:24:58,490
they tend to have lower
levels of eosinophils

601
00:24:58,490 --> 00:25:02,400
in their sputum, lower levels
of exhaled nitric oxide,

602
00:25:02,400 --> 00:25:05,943
though these eosinophils get
stuck in the airway wall.

603
00:25:06,840 --> 00:25:09,960
And so, we've been working
on that for a number of years

604
00:25:09,960 --> 00:25:12,210
and one of the reasons I got into this

605
00:25:12,210 --> 00:25:13,830
was because of an experiment we did

606
00:25:13,830 --> 00:25:17,640
with Albert Vanderbleek in pathology.

607
00:25:17,640 --> 00:25:21,120
And Albert got us to do
an allergen challenge.

608
00:25:21,120 --> 00:25:23,070
And what we did was we took people

609
00:25:23,070 --> 00:25:25,083
who are allergic to house dusts mite,

610
00:25:25,920 --> 00:25:30,180
and we stuck some house
dust mite up their nose.

611
00:25:30,180 --> 00:25:31,980
Right Olivia, we do it all the time.

612
00:25:32,970 --> 00:25:37,200
And so, the lean asthmatics
are here in the black

613
00:25:37,200 --> 00:25:39,420
and the obese asthmatics
are here in the red.

614
00:25:39,420 --> 00:25:42,270
and we measure the cytokine production

615
00:25:42,270 --> 00:25:45,990
before, 15 minutes
after, and 24 hours after

616
00:25:45,990 --> 00:25:47,970
we've given the allergen challenge.

617
00:25:47,970 --> 00:25:49,620
And much to our surprise,

618
00:25:49,620 --> 00:25:51,930
at this dose of house dust mite,

619
00:25:51,930 --> 00:25:54,420
we saw that they developed
high levels of cytokines

620
00:25:54,420 --> 00:25:59,047
such as IL-13, I think
this is IL-33, IL-13,

621
00:26:00,510 --> 00:26:03,090
and he also measured
slightly higher levels

622
00:26:03,090 --> 00:26:06,930
of ATP and hydrogen
peroxide in the airway,

623
00:26:06,930 --> 00:26:11,103
markers of suboxone stress.

624
00:26:12,480 --> 00:26:15,600
Albert went on to show,
he was very interested

625
00:26:15,600 --> 00:26:20,070
in this NADPH oxidase in the airway, DUOX.

626
00:26:20,070 --> 00:26:22,710
Albert went on to show
that the obese asthmatics

627
00:26:22,710 --> 00:26:26,040
appeared to have higher levels of leptin

628
00:26:26,040 --> 00:26:31,040
in the epithelium and higher
levels of oxidation of cystine.

629
00:26:31,320 --> 00:26:32,943
So what he did here was,

630
00:26:34,230 --> 00:26:39,230
he measured oxidized cystine
using a DCP-Bio pull down

631
00:26:39,630 --> 00:26:41,070
and detecting the strapped evidence.

632
00:26:41,070 --> 00:26:43,320
So black, sort of all these proteins

633
00:26:43,320 --> 00:26:45,030
where the cystines are oxidized.

634
00:26:45,030 --> 00:26:49,050
And you can see this is much
greater in the obese asthmatic

635
00:26:49,050 --> 00:26:51,250
than in a a healthy weight asthmatic

636
00:26:51,250 --> 00:26:53,460
or in the healthy controls.

637
00:26:53,460 --> 00:26:55,830
And he went on to do some elegant work

638
00:26:55,830 --> 00:26:59,400
using an epithelial knockout of DUOX

639
00:26:59,400 --> 00:27:01,263
to show that if he knocked out DUOX

640
00:27:01,263 --> 00:27:03,390
from the airway epithelium

641
00:27:03,390 --> 00:27:05,370
you could improve this airway reactivity

642
00:27:05,370 --> 00:27:08,070
in this obese allergic mouse model.

643
00:27:08,070 --> 00:27:11,430
And, actually, leptin appeared
to increase expression

644
00:27:11,430 --> 00:27:12,803
of DUOX in the airway.

645
00:27:12,803 --> 00:27:13,636
(phone ringing)

646
00:27:13,636 --> 00:27:15,537
(electronic voice speaking faintly)

647
00:27:15,537 --> 00:27:17,299
I'm just glad that's not me.

648
00:27:17,299 --> 00:27:19,260
(audience laughing)

649
00:27:19,260 --> 00:27:22,140
And so, in another work there,

650
00:27:22,140 --> 00:27:24,360
Yvonne Janssen-Heininger's
group has been doing.

651
00:27:24,360 --> 00:27:26,970
Yvonne has really done
some groundbreaking work

652
00:27:26,970 --> 00:27:31,170
looking at alterations in
glycolysis in the airway

653
00:27:31,170 --> 00:27:32,403
in lean asthma.

654
00:27:33,900 --> 00:27:37,140
So Pyruvate kinase is the terminal enzyme

655
00:27:37,140 --> 00:27:38,883
in the glycolytic pathway.

656
00:27:39,840 --> 00:27:44,050
And there are various Pyruvate kinase M2

657
00:27:45,750 --> 00:27:49,796
is altered structure
of the Pyruvate kinase.

658
00:27:49,796 --> 00:27:53,883
They can form dinas or
they can form tetranus,

659
00:27:56,370 --> 00:27:57,203
that's the word!

660
00:27:57,203 --> 00:27:59,400
Thank you, I'm so glad you came over.

661
00:27:59,400 --> 00:28:01,950
And depending on the confirmation,

662
00:28:01,950 --> 00:28:06,950
determines whether this goes
into oxygen phosphorylation

663
00:28:07,020 --> 00:28:12,020
or goes into form lactate and
increased airway inflammation.

664
00:28:12,855 --> 00:28:14,160
And Yvonne's group has shown

665
00:28:14,160 --> 00:28:16,467
that that's really
important in lean asthma,

666
00:28:16,467 --> 00:28:18,690
and what Alison Manuel did

667
00:28:18,690 --> 00:28:20,970
when she was working in Yvonne's lab,

668
00:28:20,970 --> 00:28:23,520
was showed that there's also dysregulation

669
00:28:23,520 --> 00:28:27,150
of this Pyruvate kinase M2 pathway

670
00:28:27,150 --> 00:28:29,700
in obese allergic asthma.

671
00:28:29,700 --> 00:28:32,280
And they use pharmacologic approaches,

672
00:28:32,280 --> 00:28:33,113
and, apparently,

673
00:28:33,113 --> 00:28:36,390
we're no longer in
communication with the company.

674
00:28:36,390 --> 00:28:40,110
But they also use genetic
knockouts to probe this pathway.

675
00:28:40,110 --> 00:28:42,030
Genetic knockouts are much harder

676
00:28:42,030 --> 00:28:43,318
in humans so advanced.

677
00:28:43,318 --> 00:28:45,083
So, it's gonna make it harder to pursue.

678
00:28:46,200 --> 00:28:48,090
Our own group has also found evidence

679
00:28:48,090 --> 00:28:52,140
of our increased airway
oxidative signaling in the airway

680
00:28:52,140 --> 00:28:55,110
and this was worked
done by Brittany Duchene

681
00:28:55,110 --> 00:28:57,240
when she was a fellow with us,

682
00:28:57,240 --> 00:29:00,060
and Sarah Caffry I
think is here somewhere,

683
00:29:00,060 --> 00:29:02,610
who's now in the second
year of medical school,

684
00:29:02,610 --> 00:29:04,323
and we had looked at,

685
00:29:05,250 --> 00:29:06,600
I use the nose a lot.

686
00:29:06,600 --> 00:29:10,170
So this is 8-isoprostanes and nasal lavage

687
00:29:10,170 --> 00:29:12,990
of lean, overweight, and obese asthmatics.

688
00:29:12,990 --> 00:29:16,470
And you can see higher levels
of these oxidative markers

689
00:29:16,470 --> 00:29:18,723
in these obese asthmatics.

690
00:29:19,980 --> 00:29:21,810
And this suggested a way

691
00:29:21,810 --> 00:29:24,540
that we could actually begin
to get at this pathway,

692
00:29:24,540 --> 00:29:25,950
because we hypothesize

693
00:29:25,950 --> 00:29:29,370
that some of these increased
airway oxidative stress

694
00:29:29,370 --> 00:29:32,460
could be coming from abnormal
mitochondrial production

695
00:29:32,460 --> 00:29:34,050
of reactive oxygen species.

696
00:29:34,050 --> 00:29:36,840
And this is work that's been led very much

697
00:29:36,840 --> 00:29:41,490
by Ravi in our group and Vikas Anathy,

698
00:29:41,490 --> 00:29:46,020
and this is using, on the top
we've got low fat diet mice,

699
00:29:46,020 --> 00:29:50,460
given PBS, house dust mite,
or given house dust mite

700
00:29:50,460 --> 00:29:54,750
plus this mitochondrial targeted
antioxidant, Mitoquinone.

701
00:29:54,750 --> 00:29:57,600
And at the bottom, you've got obese mice,

702
00:29:57,600 --> 00:30:00,870
PBS, house dust mite, given Mitoquinone,

703
00:30:00,870 --> 00:30:02,430
and what you can see here is

704
00:30:02,430 --> 00:30:04,590
one of the features of
obese allergic asthma

705
00:30:04,590 --> 00:30:05,423
that I told you about,

706
00:30:05,423 --> 00:30:09,060
where the eosinophils get
stuck in the airway wall.

707
00:30:09,060 --> 00:30:13,050
And Ravi was able to
recapitulate that feature,

708
00:30:13,050 --> 00:30:16,860
and when we gave this
mitochondrial targeted antioxidant,

709
00:30:16,860 --> 00:30:19,920
it seemed to really help with
this airway eosinophillia

710
00:30:19,920 --> 00:30:23,283
and many of the other markers
of this obese allergic asthma.

711
00:30:25,320 --> 00:30:26,220
I'm glad Ravi's here,

712
00:30:26,220 --> 00:30:29,220
because if I misquote he
can always interrupt me.

713
00:30:29,220 --> 00:30:33,437
But then he went to try
and identify targets

714
00:30:34,680 --> 00:30:37,800
that could have been a
susceptible to oxidation,

715
00:30:37,800 --> 00:30:41,880
and so, he used again this
DCP-Bio pull down method

716
00:30:41,880 --> 00:30:45,600
which lets you identify
oxidized cystine residues,

717
00:30:45,600 --> 00:30:48,810
and we're working with the
proteomic facility here

718
00:30:48,810 --> 00:30:50,850
in lean versus obese mice.

719
00:30:50,850 --> 00:30:53,520
He was able to identify proteins

720
00:30:53,520 --> 00:30:57,720
that were oxidized on the
cystine residues in the red.

721
00:30:57,720 --> 00:31:00,090
It's up-regulated by house dust mite,

722
00:31:00,090 --> 00:31:01,833
decreased by Mitoquinone,

723
00:31:03,156 --> 00:31:05,940
and in the green is just
up-regulated by house dust mite,

724
00:31:05,940 --> 00:31:07,620
and you can certainly get the impression

725
00:31:07,620 --> 00:31:09,270
in the setting of obesity,

726
00:31:09,270 --> 00:31:14,270
we've got increased upright
oxidation of more proteins

727
00:31:14,340 --> 00:31:15,810
than in the lean setting.

728
00:31:15,810 --> 00:31:16,890
And when he looked to see

729
00:31:16,890 --> 00:31:18,810
what was particularly getting oxidized

730
00:31:18,810 --> 00:31:21,690
in the setting of this
obese allergic asthma,

731
00:31:21,690 --> 00:31:23,580
he identified a number of proteins

732
00:31:23,580 --> 00:31:24,720
that are particularly involved

733
00:31:24,720 --> 00:31:27,210
in protein folding in the ER,

734
00:31:27,210 --> 00:31:30,630
suggesting that maybe
targeting ER stress response

735
00:31:30,630 --> 00:31:34,293
might be efficacious for the
treatment of obese asthma.

736
00:31:35,730 --> 00:31:37,650
Now I'm terribly pragmatic, right?

737
00:31:37,650 --> 00:31:40,140
I wanna treat my patients,
and so, at the same time

738
00:31:40,140 --> 00:31:42,960
we've got a trial that's
ongoing at the moment.

739
00:31:42,960 --> 00:31:46,350
So MitoQ is available over Amazon

740
00:31:46,350 --> 00:31:49,470
-as an anti-aging supplement.
-(audience laughing)

741
00:31:49,470 --> 00:31:51,330
So, just so you know,

742
00:31:51,330 --> 00:31:54,030
but we're actually
using this at the moment

743
00:31:54,030 --> 00:31:56,400
to treat obese asthma.

744
00:31:56,400 --> 00:31:59,370
Olivia is doing a fabulous
job of recruitment.

745
00:31:59,370 --> 00:32:00,450
We're working with Duke,

746
00:32:00,450 --> 00:32:03,060
who are not doing such a
fabulous job of recruitment,

747
00:32:03,060 --> 00:32:04,113
but we'll get there.

748
00:32:06,030 --> 00:32:11,030
So, what other treatments
do we have for obese asthma?

749
00:32:12,120 --> 00:32:15,030
And I'm gonna share with
you a couple of trials

750
00:32:15,030 --> 00:32:16,600
that we've recently published

751
00:32:18,510 --> 00:32:22,080
that shown some really
interesting results.

752
00:32:22,080 --> 00:32:27,080
So one study that we just
completed was using roflumilast,

753
00:32:27,725 --> 00:32:29,610
roflumilast is a
phosphodiesterase score inhibitor

754
00:32:29,610 --> 00:32:31,410
that's FDA approved in this country

755
00:32:31,410 --> 00:32:33,000
for the treatment of chronic bronchitis

756
00:32:33,000 --> 00:32:34,893
with recurrent exacerbations.

757
00:32:35,910 --> 00:32:37,650
It's not approved for asthma,

758
00:32:37,650 --> 00:32:40,290
but I thought I was really smart,

759
00:32:40,290 --> 00:32:43,590
because a side effect of
this drug is weight loss.

760
00:32:43,590 --> 00:32:46,020
There's actually been a study suggestion

761
00:32:46,020 --> 00:32:47,970
that improves glycemic control.

762
00:32:47,970 --> 00:32:52,830
It has some, perhaps, GLLP-1
receptor agonist type effects,

763
00:32:52,830 --> 00:32:54,690
roflumilast does have some efficacy

764
00:32:54,690 --> 00:32:55,830
in many people with asthma,

765
00:32:55,830 --> 00:32:57,630
though it's never been FDA approved.

766
00:32:57,630 --> 00:33:01,255
It's been studied in obese
mass models of asthma.

767
00:33:01,255 --> 00:33:02,820
And, actually, there's been case reports

768
00:33:02,820 --> 00:33:05,550
of using it in obese people with asthma

769
00:33:05,550 --> 00:33:07,980
and reporting improved asthma control.

770
00:33:07,980 --> 00:33:09,780
And so, we got funding for the NIH

771
00:33:09,780 --> 00:33:12,930
to do a study at six centers,

772
00:33:12,930 --> 00:33:16,290
where we randomized
people to our roflumilast

773
00:33:16,290 --> 00:33:20,550
versus placebo, and what we found here,

774
00:33:20,550 --> 00:33:25,550
the yellow is patients on roflumilast.

775
00:33:26,370 --> 00:33:29,730
The blue is patients on our placebo.

776
00:33:29,730 --> 00:33:32,310
And you can look at change
in asthma control score,

777
00:33:32,310 --> 00:33:34,050
and it doesn't take a statistician

778
00:33:34,050 --> 00:33:37,830
to tell you that this was a
pretty disappointing result.

779
00:33:37,830 --> 00:33:40,230
We did not improve asthma control.

780
00:33:40,230 --> 00:33:42,030
That was pretty disappointing.

781
00:33:42,030 --> 00:33:43,950
There was a little silver lining in this.

782
00:33:43,950 --> 00:33:46,500
There was a secondary
part of this analysis.

783
00:33:46,500 --> 00:33:47,580
We were interested,

784
00:33:47,580 --> 00:33:52,530
whether inducing weight loss
might improve asthma control,

785
00:33:52,530 --> 00:33:57,030
and so, a three point reduction
in an asthma control score

786
00:33:57,030 --> 00:33:59,220
or increase in the asthma control score

787
00:33:59,220 --> 00:34:02,790
is a clinically significant
improvement in asthma control.

788
00:34:02,790 --> 00:34:04,320
And so, we saw a clinically

789
00:34:04,320 --> 00:34:06,360
and statistically significant improvement

790
00:34:06,360 --> 00:34:10,890
in asthma control in people
who lost at least 5% weight.

791
00:34:10,890 --> 00:34:13,920
Actually, this included both
people who were on roflumilast

792
00:34:13,920 --> 00:34:14,850
as well as placebo.

793
00:34:14,850 --> 00:34:16,560
We sold this as a weight loss trial.

794
00:34:16,560 --> 00:34:19,380
So I think some people
really tried to lose weight.

795
00:34:19,380 --> 00:34:21,420
So this was really encouraging.

796
00:34:21,420 --> 00:34:23,370
However, when you're
doing a clinical trial,

797
00:34:23,370 --> 00:34:27,423
you have to look at risks
and benefits as well.

798
00:34:28,650 --> 00:34:30,270
So we looked at harms

799
00:34:30,270 --> 00:34:33,153
and there we had a real wake up call.

800
00:34:34,200 --> 00:34:38,703
So if you look at SAEs in
patients on placebo, zero.

801
00:34:39,540 --> 00:34:43,385
SAEs in patients on roflumilast, six.

802
00:34:43,385 --> 00:34:44,910
The DSMB sort of had
a field day with this,

803
00:34:44,910 --> 00:34:47,070
particularly, because we
looked at exacerbations

804
00:34:47,070 --> 00:34:48,420
from diary cards,

805
00:34:48,420 --> 00:34:51,750
and so, got this result after
completion of the study.

806
00:34:51,750 --> 00:34:54,810
And so, if you look at urgent care visits

807
00:34:54,810 --> 00:34:58,560
for asthma in patients on
placebo versus roflumilast,

808
00:34:58,560 --> 00:35:00,420
you'll see that Ramsey
is not gonna want me

809
00:35:00,420 --> 00:35:02,820
to put patients on roflumilast

810
00:35:02,820 --> 00:35:05,580
with crowding in his ED at the moment.

811
00:35:05,580 --> 00:35:07,683
So we actually made them worse.

812
00:35:09,300 --> 00:35:10,620
Why? We don't know.

813
00:35:10,620 --> 00:35:14,010
Carolyn is currently working
doing some proteomics

814
00:35:14,010 --> 00:35:15,300
and we've gone another molecule

815
00:35:15,300 --> 00:35:17,670
I think that we're gonna go after

816
00:35:17,670 --> 00:35:21,090
looking at the serum to
see why we made them worse.

817
00:35:21,090 --> 00:35:23,940
So roflumilast did not
benefit asthma control,

818
00:35:23,940 --> 00:35:26,640
it increased the risk
of asthma exacerbations,

819
00:35:26,640 --> 00:35:30,627
but 5% weight loss may be helpful.

820
00:35:30,627 --> 00:35:34,533
And so, that leads us to
lifestyle interventions.

821
00:35:35,640 --> 00:35:38,940
Now we did a lifestyle intervention

822
00:35:38,940 --> 00:35:42,510
and we were lucky enough to be
able to work with Jean Harvey

823
00:35:42,510 --> 00:35:44,110
here in the School of Nutrition.

824
00:35:45,000 --> 00:35:47,910
We actually did a six month
online weight loss study.

825
00:35:47,910 --> 00:35:50,700
We did it 40 participants,
half were recruited here

826
00:35:50,700 --> 00:35:52,863
and half were at the
University of Arizona.

827
00:35:55,264 --> 00:35:57,750
And we wanted to see if we
could produce weight loss.

828
00:35:57,750 --> 00:36:00,510
And we hypothesized
that this 5% weight loss

829
00:36:00,510 --> 00:36:03,000
might improve asthma control.

830
00:36:03,000 --> 00:36:05,400
Now, we did an online weight loss,

831
00:36:05,400 --> 00:36:08,940
patients were meeting online once a week.

832
00:36:08,940 --> 00:36:12,150
We did it at Arizona and UVM,

833
00:36:12,150 --> 00:36:15,690
and you know Arizona don't
go to daylight savings time,

834
00:36:15,690 --> 00:36:19,380
and so, we had all the groups
got completely messed up.

835
00:36:19,380 --> 00:36:20,340
There are all these things

836
00:36:20,340 --> 00:36:21,840
that you don't think about with mice

837
00:36:21,840 --> 00:36:24,845
that become really important
when you do human studies.

838
00:36:24,845 --> 00:36:25,830
(audience laughing)

839
00:36:25,830 --> 00:36:27,630
But nevertheless we managed to do it.

840
00:36:27,630 --> 00:36:30,390
I will say that this is the
hardest study that I ever did

841
00:36:30,390 --> 00:36:32,640
and if Olivia had not
been involved with this

842
00:36:32,640 --> 00:36:33,600
right from the get-go,

843
00:36:33,600 --> 00:36:36,330
we would still be recruiting
patients right now.

844
00:36:36,330 --> 00:36:39,720
Lifestyle interventions
are really, really hard.

845
00:36:39,720 --> 00:36:41,673
Nevertheless, we did it.

846
00:36:42,780 --> 00:36:47,040
And we actually got 10
out of the 43 patients

847
00:36:47,040 --> 00:36:48,390
to lose 5% of their weight.

848
00:36:48,390 --> 00:36:51,180
Now that doesn't sound like a lot, I know,

849
00:36:51,180 --> 00:36:54,933
but 23% of our people
last 5% of their weight,

850
00:36:56,250 --> 00:36:58,500
which is equivalent to the efficacy

851
00:36:58,500 --> 00:37:02,010
of things like Chantix
for smoking cessation.

852
00:37:02,010 --> 00:37:04,380
So, if we use drugs for smoking cessation,

853
00:37:04,380 --> 00:37:08,340
they work in about 22, 23% of people.

854
00:37:08,340 --> 00:37:11,070
So this lifestyle
intervention is equivalent

855
00:37:11,070 --> 00:37:12,210
to smoking cessation.

856
00:37:12,210 --> 00:37:13,833
Pulmonologists buy into that.

857
00:37:15,870 --> 00:37:17,490
But what we did see is that

858
00:37:17,490 --> 00:37:19,950
those who lost 5% of their weight,

859
00:37:19,950 --> 00:37:23,340
their asthma control
improved very significantly.

860
00:37:23,340 --> 00:37:26,190
So their asthma control
score improved by three,

861
00:37:26,190 --> 00:37:29,880
which is a clinically and
statistically significant amount.

862
00:37:29,880 --> 00:37:31,650
Their quality of life score improved

863
00:37:31,650 --> 00:37:34,383
by a clinically and
statistically significant amount.

864
00:37:35,220 --> 00:37:39,087
Their health related quality
of life measured by SF-36

865
00:37:39,087 --> 00:37:41,490
and the impact of weight
on their quality of life

866
00:37:41,490 --> 00:37:44,070
also improved by a clinically

867
00:37:44,070 --> 00:37:46,530
and statistically significant amount.

868
00:37:46,530 --> 00:37:50,700
And this is probably the
only worthwhile thing

869
00:37:50,700 --> 00:37:52,500
that I'm telling all the clinicians today,

870
00:37:52,500 --> 00:37:54,510
and it is worthwhile.

871
00:37:54,510 --> 00:37:56,190
Because I tell my patients this now,

872
00:37:56,190 --> 00:37:58,920
that if you can lose
5% of your body weight,

873
00:37:58,920 --> 00:38:02,100
that should probably
help your asthma control.

874
00:38:02,100 --> 00:38:03,180
And that's worthwhile,

875
00:38:03,180 --> 00:38:05,700
because we sit there,
we talk to our patients,

876
00:38:05,700 --> 00:38:09,600
I've got many patients
who are 300, 400 pounds,

877
00:38:09,600 --> 00:38:13,560
and I say, "If you lose weight
it's gonna help your asthma."

878
00:38:13,560 --> 00:38:14,790
And they've tried losing weight,

879
00:38:14,790 --> 00:38:16,920
and they think they've
gotta lose 200 pounds

880
00:38:16,920 --> 00:38:17,940
to improve their weight.

881
00:38:17,940 --> 00:38:21,360
But I can tell them no if
you can lose 20 pounds,

882
00:38:21,360 --> 00:38:23,220
that's gonna improve your asthma control,

883
00:38:23,220 --> 00:38:24,930
and so, I would say to the clinicians,

884
00:38:24,930 --> 00:38:27,360
that might be the only
helpful thing you've learned

885
00:38:27,360 --> 00:38:29,613
from this hour of talk, but it is helpful.

886
00:38:31,050 --> 00:38:32,070
So the other things

887
00:38:32,070 --> 00:38:34,950
that we're working to follow up from this,

888
00:38:34,950 --> 00:38:37,980
we've got a study that we're doing

889
00:38:37,980 --> 00:38:39,210
that's being headed out

890
00:38:39,210 --> 00:38:41,040
at the University of Illinois, Chicago,

891
00:38:41,040 --> 00:38:44,430
where they're looking at
improving dietary quality

892
00:38:44,430 --> 00:38:46,560
to see if that improves asthma control.

893
00:38:46,560 --> 00:38:49,890
There's a lot of data to suggest
that poor dietary quality,

894
00:38:49,890 --> 00:38:52,530
actually, is associated with
increased airway inflammation

895
00:38:52,530 --> 00:38:54,863
and impaired bronchodilator response,

896
00:38:54,863 --> 00:38:56,213
and I'm really excited about that.

897
00:38:58,200 --> 00:39:02,760
There's a lot of stuff,
Jane Gil, we have smiling.

898
00:39:02,760 --> 00:39:04,500
There is a lot of stuff all over the place

899
00:39:04,500 --> 00:39:06,180
about these weight loss drugs.

900
00:39:06,180 --> 00:39:08,640
Apparently, people can't
get the diabetes drugs,

901
00:39:08,640 --> 00:39:11,440
because everybody is on sort
of these weight loss drugs.

902
00:39:12,300 --> 00:39:14,400
There is one study going on in the US now

903
00:39:14,400 --> 00:39:16,350
using a GLP-1 receptor agonist

904
00:39:16,350 --> 00:39:18,570
that's being done out of Vanderbilt.

905
00:39:18,570 --> 00:39:21,240
I got a call with my
DCC at Hopkins next week

906
00:39:21,240 --> 00:39:23,940
to talk about whether we're
gonna try and do a study

907
00:39:23,940 --> 00:39:25,440
within our network,

908
00:39:25,440 --> 00:39:27,690
but one thing that we
have been doing here,

909
00:39:27,690 --> 00:39:29,520
it's sort of, Lisa in our mouse model,

910
00:39:29,520 --> 00:39:34,320
and this is very much led by
Carolyn with Robbie and Bella.

911
00:39:34,320 --> 00:39:36,690
There's a startup in Montreal

912
00:39:36,690 --> 00:39:41,690
that works on cannabinoid
receptor R1 inverse agonists.

913
00:39:42,000 --> 00:39:45,870
So these are drugs that have
a lot of metabolic effects.

914
00:39:45,870 --> 00:39:49,050
The airway are full of
cannabinoid receptors.

915
00:39:49,050 --> 00:39:53,070
These drugs were used I
think 10, 20 years ago,

916
00:39:53,070 --> 00:39:55,140
but the earlier iterations of these drug

917
00:39:55,140 --> 00:39:56,940
cross the blood-brain barrier

918
00:39:56,940 --> 00:40:00,030
and caused a lot of adverse
psychological effects.

919
00:40:00,030 --> 00:40:01,770
The drugs that we are using now

920
00:40:01,770 --> 00:40:04,110
don't cross the blood
brain barrier supposedly,

921
00:40:04,110 --> 00:40:06,030
and they've been developing this drug,

922
00:40:06,030 --> 00:40:08,790
for its metabolic effects and
for its weight loss effects,

923
00:40:08,790 --> 00:40:11,190
and so, we did a study with them

924
00:40:11,190 --> 00:40:13,890
where we took lean and obese mice

925
00:40:13,890 --> 00:40:16,230
and we've seen some encouraging data

926
00:40:16,230 --> 00:40:19,590
showing that we can really
improve airway reactivity,

927
00:40:19,590 --> 00:40:23,010
particularly the elastance
in these obese mice.

928
00:40:23,010 --> 00:40:26,100
Bella is busy running all the
ELIZAs trying to figure out

929
00:40:26,100 --> 00:40:28,680
what we've done with inflammation.

930
00:40:28,680 --> 00:40:30,900
And I've been having some
discussions with the company

931
00:40:30,900 --> 00:40:32,880
about whether or not we can move forward

932
00:40:32,880 --> 00:40:36,570
and do some studies in humans with this.

933
00:40:36,570 --> 00:40:38,643
So watch this space.

934
00:40:41,190 --> 00:40:45,060
So it's 5:20, everybody's getting tired.

935
00:40:45,060 --> 00:40:47,700
So I just wanna just
leave you with a summary,

936
00:40:47,700 --> 00:40:50,700
if you completely slept
through the last 45 minutes

937
00:40:50,700 --> 00:40:52,500
-and I wouldn't blame you.
-(audience laughing)

938
00:40:52,500 --> 00:40:56,430
So obesity is associated with
severe poor asthma control.

939
00:40:56,430 --> 00:41:01,020
60% of poorly controlled
asthmatics in the US are obese.

940
00:41:01,020 --> 00:41:03,660
They have about a fivefold
risk of hospitalization,

941
00:41:03,660 --> 00:41:05,220
compared with lean asthmatics,

942
00:41:05,220 --> 00:41:07,080
so when you see these
patients in your clinic,

943
00:41:07,080 --> 00:41:08,790
they have a real disease.

944
00:41:08,790 --> 00:41:10,020
They don't respond as well

945
00:41:10,020 --> 00:41:12,393
to the medications that
we use to treat them.

946
00:41:13,380 --> 00:41:16,500
This disease is associated with
altered metabolic function.

947
00:41:16,500 --> 00:41:19,170
We don't really understand what
that's doing in the airway,

948
00:41:19,170 --> 00:41:21,630
but we do know that they've
got an increased tendency

949
00:41:21,630 --> 00:41:23,400
towards this air trapping

950
00:41:23,400 --> 00:41:25,020
and in data I didn't show you,

951
00:41:25,020 --> 00:41:26,550
it's actually more difficult for them

952
00:41:26,550 --> 00:41:29,433
to recruit their airway
after bronchoconstriction.

953
00:41:30,360 --> 00:41:32,100
There's this novel form of asthma

954
00:41:32,100 --> 00:41:34,230
and then there's people that are obese,

955
00:41:34,230 --> 00:41:37,230
and their allergic asthma
is really much changed

956
00:41:37,230 --> 00:41:39,540
when they develop obesity.

957
00:41:39,540 --> 00:41:41,730
We've been looking at new
approaches to treatments,

958
00:41:41,730 --> 00:41:46,560
CPAP, MitoQ, CB1 receptor,
inverse agonists,

959
00:41:46,560 --> 00:41:47,580
not the roflumilast,

960
00:41:47,580 --> 00:41:50,370
we're not gonna take that
into a follow up trial,

961
00:41:50,370 --> 00:41:53,040
and lifestyle considerations.

962
00:41:53,040 --> 00:41:53,873
The one thing,

963
00:41:53,873 --> 00:41:56,610
I think 5% weight loss
may be really helpful

964
00:41:56,610 --> 00:41:57,600
and I'm really looking forward

965
00:41:57,600 --> 00:41:58,650
to completing the studies

966
00:41:58,650 --> 00:42:00,240
that we're doing on dietary quality,

967
00:42:00,240 --> 00:42:03,873
because I think that will
be really interesting too.

968
00:42:05,010 --> 00:42:07,350
So I would like to acknowledge,

969
00:42:07,350 --> 00:42:10,290
I think, if it takes a
village to raise a child,

970
00:42:10,290 --> 00:42:13,350
it takes a city for me to do my work.

971
00:42:13,350 --> 00:42:16,590
A huge thank you,
obviously, NIH and funders

972
00:42:16,590 --> 00:42:18,600
and the American Lung Association.

973
00:42:18,600 --> 00:42:21,867
There are so many people
sitting around this room

974
00:42:21,867 --> 00:42:22,700
and who are not in this room

975
00:42:22,700 --> 00:42:24,360
who've given me so much
help over the years.

976
00:42:24,360 --> 00:42:25,620
Thank you all.

977
00:42:25,620 --> 00:42:27,240
And I've got a number of collaborators

978
00:42:27,240 --> 00:42:28,770
around the country

979
00:42:28,770 --> 00:42:31,020
without whom there really
wouldn't be much data

980
00:42:31,020 --> 00:42:32,640
to show on this slide.

981
00:42:32,640 --> 00:42:35,493
So thank you, and I'd be
happy to take any questions.

982
00:42:36,758 --> 00:42:39,758
(audience clapping)