Suppression of acute lung injury in mice by an inhibitor of phosphodiesterase type 4.
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 (TNFalpha) levels induced by LPS and zymosan treatment, measured after 2.5 h. The role of endogenous TNFalpha in the induction of lung injury was therefore assessed. Blockade of endogenous TNFalpha by treatment with the soluble receptor p55-IgG fusion protein or an anti-murine TNFalpha monoclonal antibody, TN3. 19.12, had no protective effect against LPS and zymosan-induced lung injury. This suggests that there is a disassociation between TNFalpha 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 results of the present study suggest that use of agents such as rolipram that inhibit PDE4 may have a therapeutic role in treatment of acute lung injury, since we have shown that it is effective in attenuation of neutrophil activation even after sequestration. However, its effect appears to be independent of TNFalpha inhibition.
Miotla
J M
JM
Applied Pharmacology, Imperial College School of Medicine, National Heart and Lung Institute, London, United Kingdom.
Teixeira
M M
MM
Hellewell
P G
PG
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009504:Neutrophils; D010726:Phosphodiesterase Inhibitors / Q000627:therapeutic use*; D011652:Pulmonary Circulation / Q000187:drug effects; D011760:Pyrrolidinones / Q000627:therapeutic use*; D012128:Respiratory Distress Syndrome / Q000139:chemically induced / Q000188:drug therapy*; D020889:Rolipram; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis; D015054:Zymosan / Q000494:pharmacology
D008070:Lipopolysaccharides; D010726:Phosphodiesterase Inhibitors; D011760:Pyrrolidinones; D014409:Tumor Necrosis Factor-alpha; D015054:Zymosan; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram