Therapeutic potential of a new phosphodiesterase inhibitor in acute lung injury.
The effects of LASSBio596, a phosphodiesterase type-4 and -5 inhibitor, were tested in Escherichia coli lipopolysaccharide (LPS)-induced acute lung injury. Twenty-four BALB/c mice were randomly divided into four groups. In the control group, saline (0.05 mL) was injected intratracheally (i.t.). The LPS group received LPS (10 microg i.t., 0.05 mL). In the LASSBio596 groups, LASSBio596 (10 mg x kg(-1), 0.2 mL) was injected intraperitoneally 1 h before or 6 h after LPS administration. After 24 h, in vivo (lung resistive and viscoelastic pressures, and static and dynamic elastances) and in vitro (tissue resistance, elastance and hysteresivity) pulmonary mechanics, lung morphometry and collagenous fibre content were computed. Neutrophils and tumour necrosis factor (TNF)-alpha levels were evaluated in the bronchoalveolar lavage fluid. LASSBio596 prevented the changes in lung mechanics, and inhibited neutrophilic recruitment, TNF-alpha release, bronchoconstriction, alveolar collapse and the increment of collagen fibre content induced by LPS, independently of the moment of injection. In conclusion, LASSBio596 modulated the lung inflammatory process and had the potential to block fibroproliferation. Thus, agents that inhibit phosphodiesterase 4 and 5 simultaneously may be a useful adjunct therapy for acute lung injury.
Rocco
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PR
Laboratory of Respiration Physiology, Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
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D000704:Analysis of Variance; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D008070:Lipopolysaccharides; D051379:Mice; D008807:Mice, Inbred BALB C; D009504:Neutrophils / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010879:Piperazines / Q000737:chemistry*; D011687:Purines; D012128:Respiratory Distress Syndrome / Q000473:pathology* / Q000517:prevention & control*; D012129:Respiratory Function Tests; D015656:Respiratory Mechanics; D000068677:Sildenafil Citrate; D018709:Statistics, Nonparametric; D013450:Sulfones; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D008070:Lipopolysaccharides; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D014409:Tumor Necrosis Factor-alpha; D013792:Thalidomide; D000068677:Sildenafil Citrate