In the original proposal, we were able to describe the effects of endotoxemia on lung mechanics in the unanesthetized sheep (an animal model of the adult respiratory distress syndrome--ARDS). We defined two possibly interrelated mechanisms that may be responsible, at least in part, for the alterations in lung mechanics observed following endotoxemia--cyclooxygenase products of arachidonate metabolism and inflammatory cells (especially granulocytes). We also demonstrated that endotoxemia acutely increased pulmonary responsiveness to aerosol histamine while granulocyte depletion decreased pulmonary responsiveness to aerosol histamine. These results generated a new hypothesis central to this competing renewal. We hypothesize that pulmonary inflammation mediates the alterations in lung mechanics associated with two interrelated clinical problems--ARDS and altered airway responsiveness as is observed in asthma. In this proposal, we expand our models of lung injury associated with pulmonary inflammation to two new models other than endotoxemia--phorbol myristate acetate (PMA) and zymosan activated plasma (ZAP) infusions. We propose to address our specific goals and hypotheses through the use of new techniques which allow us to more accurately measure changes in lung mechanics, pulmonary hemodynamics and lung fluid and solute exchange (including retrograde airway catheters and epithelial permeability, improved analytic methods and quantitative morphometrics). We will continue to try to elucidate important mechanisms responsible for the pathologic changes associated with endotoxemia, PMA, ZAP and altered airway responsiveness through assays of potential mediators, the use of specific blocking agents, granulocyte and platelet depletion and infusions and by studying the effects of infused potential mediators.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL027274-05
Application #
3339039
Study Section
Respiratory and Applied Physiology Study Section (RAP)
Project Start
1981-04-01
Project End
1987-03-31
Budget Start
1985-04-01
Budget End
1986-03-31
Support Year
5
Fiscal Year
1985
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37203
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Snapper, J R; Lu, W; Lefferts, P L et al. (1998) Effect of platelet-activating factor-receptor antagonism on endotoxin-induced lung dysfunction in sheep. J Appl Physiol 84:1610-4
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Conary, J T; Parker, R E; Christman, B W et al. (1994) Protection of rabbit lungs from endotoxin injury by in vivo hyperexpression of the prostaglandin G/H synthase gene. J Clin Invest 93:1834-40
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Kuratomi, Y; Lefferts, P L; Christman, B W et al. (1993) Effect of a 5-lipoxygenase inhibitor on endotoxin-induced pulmonary dysfunction in awake sheep. J Appl Physiol 74:596-605

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