Abstract

Our hypothesis is that interleukin-1 (IL-1) induced neutrophil recruitment and activation with release of damaging oxygen radicals (02*) and/or elastase is a fundamental feature of ARDS. We propose that endotoxin (LPS) and IL-1 initiate neutrophil recruitment and activation by production of LTB4, IL-8 and increased xanthine oxidase (XO) activity leading to superoxide (O2) activated chemotaxins. Activated neutrophils inflict oxidative damage reflected by glutathione oxidation, antiprotease inactivation, vitamin E depletion and lipid peroxidation. These events cause acute lung injury, kidney damage, more neutrophil influx and lacerations in neutrophils. Concomitant increases in markers (MnSOD, catalase, GSSG, MPO, elastase-alpha1Pi complexes, and H202 and other factors) reflect and impact ARDS progression.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Specialized Center (P50)
Project #
5P50HL040784-09
Application #
2028390
Study Section
Special Emphasis Panel (ZHL1-CSR-B (M2))
Project Start
1988-12-01
Project End
1998-11-30
Budget Start
1996-12-01
Budget End
1997-11-30
Support Year
9
Fiscal Year
1997
Total Cost
Indirect Cost

  Institution

Name
University of Colorado Denver
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
065391526
City
Aurora
State
CO
Country
United States
Zip Code
80045

  Publications

Moore, Frederick A (2010) Presidential address: imagination trumps knowledge. Am J Surg 200:671-7
Hybertson, Brooks M; Chung, Jin H; Fini, Mehdi A et al. (2005) Aerosol-administered alpha-tocopherol attenuates lung inflammation in rats given lipopolysaccharide intratracheally. Exp Lung Res 31:283-94
Moss, Marc; Parsons, Polly E; Steinberg, Kenneth P et al. (2003) Chronic alcohol abuse is associated with an increased incidence of acute respiratory distress syndrome and severity of multiple organ dysfunction in patients with septic shock. Crit Care Med 31:869-77
Hybertson, Brooks M; Jepson, Eric K; Allard, Jenny D et al. (2003) Transforming growth factor beta contributes to lung leak in rats given interleukin-1 intratracheally. Exp Lung Res 29:361-73
Gao, Bifeng; Flores, Sonia C; Leff, Jonathan A et al. (2003) Synthesis and anti-inflammatory activity of a chimeric recombinant superoxide dismutase: SOD2/3. Am J Physiol Lung Cell Mol Physiol 284:L917-25
Nick, Jerry A; Young, Scott K; Arndt, Patrick G et al. (2002) Selective suppression of neutrophil accumulation in ongoing pulmonary inflammation by systemic inhibition of p38 mitogen-activated protein kinase. J Immunol 169:5260-9
Lee, Young M; Hybertson, Brooks M; Cho, Hyun G et al. (2002) Platelet-activating factor induces lung inflammation and leak in rats: hydrogen peroxide production along neutrophil-lung endothelial cell interfaces. J Lab Clin Med 140:312-9
Suratt, B T; Young, S K; Lieber, J et al. (2001) Neutrophil maturation and activation determine anatomic site of clearance from circulation. Am J Physiol Lung Cell Mol Physiol 281:L913-21
Avdi, N J; Nick, J A; Whitlock, B B et al. (2001) Tumor necrosis factor-alpha activation of the c-Jun N-terminal kinase pathway in human neutrophils. Integrin involvement in a pathway leading from cytoplasmic tyrosine kinases apoptosis. J Biol Chem 276:2189-99
Nick, J A; Young, S K; Brown, K K et al. (2000) Role of p38 mitogen-activated protein kinase in a murine model of pulmonary inflammation. J Immunol 164:2151-9

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