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.