Although the pathogenesis of ARDS has been extensively studied the cellular and molecular events that lead to the acute lung injury in humams are not yet sufficiently defined to allow us either to predict who will develop ARDS or how to treat it. We propose to study patients at risk for developing ARDS and patients with well-established ARDS to understand better the pathogenesis and resolution of the acute lung injury. Based on available ARDS patient data and in vivo and in vitro data from animal models of acute lung injury, we hypothesize that the development of ARDS is the result of synergism between two or more leukocyte stimulating factors and that the propagation of the acute lung injury is dependent on the neutrophil. We specifically propose that endotoxin may cause neutrophil sequestration in the lungs and the stimulation of alveolar macrophages to produce chemotactic factors for neutrophils. Concommitant activation of complement could enhance neutrophil sequestration and, with the alveolar macrophage derived chemotactic factors, could cause neutrophil migration into the alveoli. The combination of LPS and chemotactic factors results in enhanced release of porteases, oxidants, and lipid inflammatory mediators from neutrophils which could both further recruit neutrophils and cause alveolar damage. Variation in cellular responsiveness to endotoxin could enhance or quench this cascade. The disappearance of complement fragments and endotoxin from the systemic circulation would halt the cascade and allow for the early fibroblast and the early and late type II cell proliferation. If allowed to proceed unhampered the repair process may restore normal lung architecture. The specific questions which will be answered include (a) Can the development of ARDS be predicted based on the presence of complement fragments and endotoxin in plasma and/or peripheral cellular responsiveness to endotoxin? (b) Which inflammatory mediators are present in ARDS and do their relative amounts relate to circulating levels of complement and endotoxin? (c) How is the repair phase of the acute lung injury initiated, and what factors influence the outcome of the repair process? The answers to these questions will provide us with a better understanding of the pathogenesis and resolution of ARDS and of how and when to direct therapeutic modalities.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Clinical Investigator Award (CIA) (K08)
Project #
Application #
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
National Jewish Health
United States
Zip Code
Parsons, P E; Moss, M; Vannice, J L et al. (1997) Circulating IL-1ra and IL-10 levels are increased but do not predict the development of acute respiratory distress syndrome in at-risk patients. Am J Respir Crit Care Med 155:1469-73
Moss, M; Bucher, B; Moore, F A et al. (1996) The role of chronic alcohol abuse in the development of acute respiratory distress syndrome in adults. JAMA 275:50-4
Moss, M; Gillespie, M K; Ackerson, L et al. (1996) Endothelial cell activity varies in patients at risk for the adult respiratory distress syndrome. Crit Care Med 24:1782-6
Poggetti, R S; Moore, E E; Moore, F A et al. (1995) Quantifying oxidative injury in the liver. Am J Physiol 268:G471-9
Parsons, P E; Gillespie, M M; Moore, E E et al. (1995) Neutrophil response to endotoxin in the adult respiratory distress syndrome: role of CD14. Am J Respir Cell Mol Biol 13:152-60
Moss, M; Goodman, P L; Heinig, M et al. (1995) Establishing the relative accuracy of three new definitions of the adult respiratory distress syndrome. Crit Care Med 23:1629-37
Moss, M; Ackerson, L; Gillespie, M K et al. (1995) von Willebrand factor antigen levels are not predictive for the adult respiratory distress syndrome. Am J Respir Crit Care Med 151:15-20
Leff, J A; Parsons, P E; Day, C E et al. (1993) Serum antioxidants as predictors of adult respiratory distress syndrome in patients with sepsis. Lancet 341:777-80
Poggetti, R S; Moore, F A; Moore, E E et al. (1992) Simultaneous liver and lung injury following gut ischemia is mediated by xanthine oxidase. J Trauma 32:723-7;discussion 727-8
Poggetti, R S; Moore, F A; Moore, E E et al. (1992) Liver injury is a reversible neutrophil-mediated event following gut ischemia. Arch Surg 127:175-9

Showing the most recent 10 out of 18 publications