Abstract
The release of free radicals and pro-inflammatory cytokines such as nitric oxide (NO) and tumor necrosis factor alpha (TNFα) is commonly observed in adult respiratory distress syndrome (ARDS) following infection or exposure to microbial products. The aim of this study was to scrutinize the involvement of NO in ARDS in a mouse model determined by the sequential exposure to lipopolysaccharide (LPS) and formyl-norleucyl-phenylalanine (FNLP). Nitrite measurements in bronchoalveolar lavage fluids (BALF) and sera demonstrated that exposure to microbial products elicits large amounts of NO in LPS/FNLP-challenged mice. This release was significantly inhibited by infusion with the inducible NO synthase antagonist, aminoguanidine (AG). Our results show that LPS/FNLP exposure induces lung damage as demonstrated by protein and lactate dehydrogenase (LDH) increases in BALF. Liver damage was also detected in LPS/FNLP-challenged mice with increases in serum ornithine-carbamoyltranferase (OCT) levels. LPS/FNLP infusion led to elevated levels of the cytokines interleukin-6 (IL-6) and tumor necrosis factor alpha (TNFα) in the sera. LPS/FNLP also led to neutrophil adhesion in the lung vasculature, as seen by increased levels of myeloperoxydase. Interestingly, inhibition of NO release in challenged mice led to an important increase in markers of tissue damage in the lungs and livers, but a decrease in neutrophil recruitment. Infusion of AG in LPS/FNLP-challenged mice led to a much increased level of sera TNFα. These data suggest that after exposure to microbial products, NO generated as a result of activation of the inducible NO synthase blocks the full expression of tissue damage in the lungs.
Similar content being viewed by others
References
Moncada, S. andE. A. Higgs. 1991. Endogenous nitric oxide: Physiology, pathology and clinical relevance.Eur. J. Clin. Invest. 21:361–374.
Palmer, R. M. J. andS. Moncada. 1989. A novel citrulline-forming enzyme implicated in the formation of nitric oxide by vascular endothelial cell.Biochem. Biophys. Res. Commun. 158:348–352.
Hibbs, J. B., R. R. Taintor, Z. Vavrin, E. M. Rachlin. 1988. Nitric oxide; A cytotoxic activated macrophage effector molecule.Biochem. Biophys. Res. Commun. 157:87–94.
Rees, D. D., S. Cellen, R. M. J. Palmer, andS. Moncada. 1990. Dexamethasone prevents the induction by endotoxin of a nitric oxide synthase and the associated effects on vascular tone.Biochem. Biophys. Res. Commun. 173:541–547.
Fein, A. M., M. Lippmann, A. H. Holtzman, A. Eliraz, andS. K. Goldberg. 1983. The risk factors, incidence and prognosis of ARDS following septicemia.Chest 83:40–42.
Hasleton, P. S. 1983. Adult respiratory distress syndrome: A review.Histopathology 7:307–332.
Denis, M., L. Guojian, M. Widner, andA. Cantin. 1993. A mouse model of lung injury induced by microbial products: Implication of tumor necrosis factor.Am. J. Respir. Cell Mol. Biol. 10:658–664.
Nathan, C. 1992. Nitric oxide as a secretory product of mammalian cells.FASEB J. 6:3051–3058.
van Dervort, A. L., L. Yan, P. J. Madara, J. P. Cobb, R. A. Wesley, C. C. Corriveau, M. M. Troper, andR. L. Danner. 1994. Nitric oxide regulates endotoxin-induced TNFα production by human neutrophils.J. Immunol. 152:4102–4109.
Marcinkiewicz, J. andB. M. Chain. 1993. Differential regulation of cytokine production by nitricoxide.Immunology 80:146–150.
Billiar, T. R., R. D. Curran, B. G. Harbrecht, D. Stuehr, A. J. Demetris, R. L. Simmons, 1990. Modulation of nitrogen oxide synthesisin vivo: NG-monomethyl-L-arginine inhibits endotoxin-induced nitrite/nitrate biosynthesis while promoting hepatic damage.J. Leukocyte Biol. 48:565–569.
Florquin, S., Z. Amraoui, C. Dubois, J. Decuyper, andM. Goldman. 1994. The protective role of endogenously synthesized nitric oxide in staphylococcal endotoxin B-induced shock in mice.J. Exp. Med. 180:1153–1158.
Ianaro, A., C. A. O'donnell, M. Di Rosa, andF. Y. Liew. 1994. A nitric oxide synthase inhibitor reduces inflammation, down regulates inflammatory cytokines and enhances interleukin-10 production in carrageenin-induced oedema in mice.Immunology 82:370–375.
Mulligan, M. S., J. S. Warren, C. W. Smith, D. C. Anderson, C. G. Yeh, A. R. Rudolph, andP. A. Ward. 1992. Lung injury after deposition of IgA immune complexes, requirements for CD18 and L-arginine.J. Immunol. 148:3086–3092.
Mulligan, M. S., S. Moncada, andP. A. Ward, 1992. Protective effects of inhibition of nitricoxide synthase in immune complex-induced vasculitis.Br. J. Pharmacol. 107:1159–1162.
Kanner, J., S. Harel, andR. Granit, 1991. Nitric oxide as an anti-oxidant.Arch. Biochem. Biophys. 289:130–136.
Lander, H. M., P. Sehajphal, D. M. Levine, andA. Novogrodsky. 1993. Activation of human peripheral blood mononuclear cells by nitric oxide-generating compounds.J. Immunol. 150:1509–1513.
Kubes, P., M. Suzuki, andD. N. Granger. 1991. Nitric oxide; An endogenous modulator of leukocyte adhesion.Proc. Natl. Acad. Sci. 88:4651–4655.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Pheng, L.H., Francoeur, C. & Denis, M. The involvement of nitric oxide in a mouse model of adult respiratory distress syndrome. Inflammation 19, 599–610 (1995). https://doi.org/10.1007/BF01539139
Issue Date:
DOI: https://doi.org/10.1007/BF01539139