Transcript Research Template - UMKC School of Medicine

The pulmonary vessel adventitia: role in pathology of fat embolism
Susamita Kesh, Agostino Molteni, Todd M. Stevens, Betty Herndon
UMKC School of Medicine
Introduction
 The pulmonary arterial wall consists of 3 layers,
intima, media, adventitia
 Smooth muscle cells & endothelial cells make up the
first 2 layers, the adventitia is the most complex
 Adventitia contains fibroblasts, blood and lymphatics,
adrenergic nerves, progenitor and immune cells
 It is the major injury-sensing tissue of the vessel wall
 Adventitia is activated by hormones, inflammation,
hypoxia, foreign substances in blood and responds by
upregulating cytokines and chemokines that regulate
the vessel wall
 Adventitia becomes, when blood pressure↑, the most
important part of the blood vessel due to its stiffening,
secretion, and the presence of inflammatory cells.
 Hypothesis: The pulmonary adventitia is crucial to
the lung pathology induced by fat embolism.
intima
media
Results
Lung Adventitia
The adventitia consists of an extracellular scaffold containing
fibroblasts, blood and lymphatic vessels, nerves, progenitor and
immune cells
This makes the adventitia the most complex compartment of
the blood vessel wall
Recent published data shows that the adventitia is a center for
storage, integration and release of the key components of blood
vessel function:
Adventitial cells are often the first vascular wall cells to be
activated
They are early in cell proliferation
They express many important proteins (adhesion,
extracellular matrix)
Adventitia secretes chemokines, cytokines, angiogenic proteins
that effect other cell walls
In summary, the adventitia regulates vascular structure and
function
adventitia
Sub-endothelial zone
Methods
Adventitia stem &
progenitor cells
Fat embolism model and adventitia
In humans fat embolism (FE: from marrow lipids
reaching the lung secondary to long bone fracture) is
seen early post injury as respiratory insufficiency
which clears without intervention
It is commonly believed that there are no long term
pulmonary sequelae after FE—although human
studies have shown decreased PFTs in groups with
healed long bone fractures compared to controls
To further evaluate responses of pulmonary vessel
components to FE, this study attempts to evaluate
changes in pulmonary vessel adventitia following a
model of long bone fracture: fat embolism complicated
by a “second hit”
36 rats were administered fat embolism model
(triolein i.v.) or saline, followed at 6 weeks by LPS i.p.
or saline, with lung study at 24 hr
Bronchoalveolar lavages
Groups: 18 saline i.v. or 18 triolein i.v. (fat
embolism and controls)
Each of these groups were further divided into
saline or LPS i.p. treated animals at 6 weeks.
Necropsy was performed 48 hours later.
 4-5 digital photos at 400 x were taken of each
lung section
 Lumen, media and adventitia diameters were
measured for each lung
 Lumen-media ratio and media-adventitia
ratios were calculated
 The vessel ratios were compared by group
using Statistica parametric comparison
 Adventitia diameters were statistically
analyzed separately
•
•
•
•
%PMN in BAL
Saline + 6 wk + saline @ 24 hr
3.5%
Triolein + 6 wk + saline @ 24 hr
5.5%
Saline + 6 wk + LPS
@ 24 hr
11.1%
Triolein + 6 wk + LPS @ 24 hr
14.4%
• ~ 15% elevation in BAL PMN by triolein 6
weeks earlier and ~ threefold elevation by LPS
, 24 hr before BAL counts
• Macrophages and lymphocytes were not
significantly different by treatment group
LPS at 6 wk
(right) increases
inflammation but
does not change
the vessel.
control artery
with adventitia
H&E 400x
Triolein (fat
embolism model)
stimulates vessel
adventitia; added
LPS shows similar
effect H&E 400x
Triolein (fat embolism
model) stimulates
vessel adventitia;
added LPS shows
similar effect
trichrome 400x
Summary /Conclusion
adventitial change in a model of fat embolism
was measured
both initial insult (fat embolism) and a second
hit (LPS at 6 weeks) produce effects on
pulmonary vasculature and the adventitia in
particular
This and previous work suggest an effect of the
renin-angiotensin system on lung vessels in this
model of fat embolism
References
1.Majesky MW et al. Nature Biotechnology
30:152-4, 2012
2.Grudzinska MK et al. Arterioscler Thromb Vasc
Biol 33: 1271-9, 2013
3.Tilki D, et al, Trends in Molecular Med 15L 501-8,
2009
4.Majesky MW et al, Cells,Tissues,Organs 195:7381, 2012