Chronic Conditions in Older Adults and Susceptibility to Environmental Exposures Mark W. Frampton MD Pulmonary & Critical Care Division University of Rochester Medical Center
Jan 20, 2016
Chronic Conditions in Older Adults and Susceptibility to Environmental
Exposures
Mark W. Frampton MD
Pulmonary & Critical Care Division
University of Rochester Medical Center
Questions About Susceptibility to Air Pollution in the Elderly
• What are the conditions involved?
• How does air pollution affect patients with these conditions?
• Can air pollution cause these conditions?
Diseases of Concern
• Obstructive Lung Disease
• Cardiovascular disease
• Infection
• Cancer
• Others that haven’t been studied?– Obstructive sleep apnea– Pulmonary fibrosis– Chronic cough
Obstructive Lung Diseases
• Asthma
• COPD, Chronic Bronchitis
• Cystic Fibrosis
• Smoking?
The Normal Airway
Mucosal Inflammation
Increased Secretions
The Airway in Asthma
Spirometry Flow-Volume LoopNormal COPD
Dosimetry & Fate of Deposited PM
NORMAL
COPD
PM Xenon
0
0.05
0.1
0.15
0.2
0.25
0.3
Normal
SAD
CO
PD
Diameter = 1 µm
Smoker
Asthma
Fractional Deposition
Bennett et al., 1993, 2002 Kim et al., 1997
Rest Exercise0
0.2
0.4
0.6
0.8
1Healthy
Asthma
p<0.001
Total Respiratory Deposition of UFP
p<0.001
Respiratory Deposition of UFP
Cardiovascular Disease
• Atherosclerosis• Coronary artery disease• Myocardial infarction• Congestive heart failure• Cardiac arrhythmias• Peripheral vascular disease• Diabetes• Pulmonary hypertension
Increase in Atherosclerosis with 10 µg/m3 increase in
PM2.5
Künzli et al., EHP 2004
Canine Myocardial Ischemia Model
• Implantation of balloon occluder for coronary artery occlusion
• 5 min occlusions with CAPs or Sham exposures.
Wellenius et al., 2002
Wellenius et al., 2002
Endothelial Dysfunction in AtherosclerosisRoss et al., NEJM 1999
Early AtherosclerosisDiaz et al., NEJM 1997
How do inhaled particles cause effects in blood vessels?
Science, 2005
Does exposure to UFP alter endothelial function in the pulmonary circulation?
Exposure to Carbon UFP
• Count median diameter ~26 nm, GSD ~1.6
• 2 hrs by mouthpiece
• Intermittent exercise
Experimental Protocol
-2 0 2 4 6 24 48
UFP or Air
SymptomsPhlebotomyExhaled NODLCOSpirometryOximetry
= Resting HRVFlow-mediated dilatation
=
Leukocyte Recruitment in Inflammation
Inflammation: The Leukocyte Adhesion Cascade
Inflammation is a defense reaction caused by tissue damage or injury, characterized by redness, heat, swelling, and pain. The primary objective of inflammation is to localize and eradicate the irritant and repair the surrounding tissue. For the survival of the host, inflammation is a necessary and beneficial process. The inflammatory response involves three major stages: first, dilation of capillaries to increase blood flow; second, microvascular structural changes and escape of plasma proteins from the bloodstream; and third, leukocyte transmigration through endothelium and accumulation at the site of injury.
The leukocyte adhesion cascade is a sequence of adhesion and activation events that ends with extravasation of the leukocyte, whereby the cell exerts its effects on the inflamed site. At least five steps of the adhesion cascade are , ,
, , and . Each of these five steps appears to be necessary for effective leukocyte recruitment, because blocking any of the five can severely reduce leukocyte accumulation in the tissue. These steps are not phases of inflammation, but represent the sequence of events from the perspective of each leukocyte. At any given moment, capture, rolling, slow rolling, firm adhesion and transmigration all happen in parallel, involving different leukocytes in the same microvessels.
capture rolling slow rolling firm adhesion transmigration
The roles of adhesion molecules in acute and chronic inflammation have been investigated using model systems and microcirculation studies. The ultimate goal of inflammation research is to develop methods to control inflammation by
modulating or blocking leukocyte adhesion to the endothelium. These ideas developed by basic research contribute to contemporary research projects developing . Anti-inflammatory agents function as blockers, suppressors, or modulators of the inflammatory response.
in vitro in vivo
anti- inflammatory drugs
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Pulmonary Diffusing Capacity for CO (DLCO):
Sensitive to changes in pulmonary capillary blood volume
*
Ch
ang
e in
DL
CO
(m
l/min
/mm
Hg
)
-3
-2
-1
0
1
Air
UFP
21 h 45 h
Change in CO Diffusion Capacity After Exposure to 50 mg/m3 UFP
Does exposure to UFP alter endothelial function in the systemic circulation?
Systemic Endothelial Function:Flow-Mediated Vasodilatation
AM
PM
Monocyte
NO
OONO-
CD11a/CD18
TFTF
Fibrin &platelet deposition
Before Exposure
After Exposure
NO
Platelets
Proposed Mechanisms for Vascular Effects of UFP
Conclusions: PM Effects on Chronic Conditions in the Elderly
• PM exacerbates obstructive lung disease• PM triggers cardiac events• PM may alter pulmonary & systemic
endothelial function• PM may accelerate atherosclerosis• The key PM characteristics remain
unknown• Likely other affected conditions