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Suppression of acute lung injury in mice by an inhibitor of phosphodiesterase type 4

By Jadwiga M. Miotla, Mauro M. Teixeira and Paul G. Hellewell

Abstract

The present study has investigated the therapeutic potential of a type 4 phosphodiesterase (PDE) inhibitor, rolipram, in experimental lung injury. Acute lung injury was induced in the mouse by combined treatment with lipopolysaccharide (LPS; 10 mg/kg, i.v.) and zymosan (3 mg/kg, i.v.), and assessed using extravascular albumin accumulation; neutrophil sequestration in pulmonary capillaries was also measured. The results show that pretreatment with rolipram (5 mg/kg, i.p.) was protective against the induction of lung injury by combined LPS and zymosan; extravascular albumin accumulation was reduced by 89 % and neutrophil sequestration in lung tissue, as assessed by lung myeloperoxidase (MPO) activity was reduced by 75%. Pretreatment with rolipram also attenuated increases in serum tumor necrosis factor alpha (TNF�) levels induced by LPS and zymosan treatment, measured after 2.5 h. The role of endogenous TNF � in the induction of lung injury was therefore assessed. Blockade of endogenous TNF � by treatment with the soluble receptor p55-IgG fusion protein or an anti-murine TNF � monoclonal antibody, TN3.19.12, had no protective effect against LPS and zymosan-induced lung injury. This suggests that there is a disassociation between TNF � production and the induction of injury in this model. Administration of rolipram after LPS and before zymosan treatment obliterated the increase in pulmonary vascular permeability, but its effect on sequestration of neutrophils in pulmonary microvessels, as measured by MPO, was less marked. The result

Year: 1998
DOI identifier: 10.1165/ajrcmb.18.3.2913
OAI identifier: oai:CiteSeerX.psu:10.1.1.318.955
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