PROTECTIVE EFFECT OF TAXOL ON LIPOPOLYSACCHARIDE (LPS)‐INDUCED ACUTE LUNG INJURY

Our prior study demonstrated that similar to actin cytoskeleton, microtubule (MT) network is a key participant in the regulation of endothelial (EC) permeability. Disassembly of MT by pharmacological inhibitors nocodazole and vinblastineresults in rearrangement of actin cytoskeleton, stressfiber formation, EC contraction, and increased permeability. MT‐stabilizing agent, Taxol ® , prevented EC barrier dysfunction induced by MT inhibitors and significantly attenuated permeability induced by proinflammatory agonists such as thrombin in cell culture model. We hypothesized that Taxol ® may prevent inflammation and vascular leak associated with lung injury. The effect of Taxol ® was assessed employing a murine model of acute lung injury induced by intratracheal LPS administration (2.5 mg/kg). Our data demonstrate that a single dose of Taxol ® (8.5mg/kg, intravenous), injected simultaneously with LPS administration, dramatically reduced LPS‐induced inflammatory histological changes in lung parenchyma, decreased infiltration of proteins (40%, P< 0.001) and inflammatory cells (51%, P< 0.01) in bronchoalveolar lavage (BAL) and LPS‐mediated extravasation of Evans blue dye albumin in lung tissue. Taxol ® also significantly reduced LPS‐induced release of inflammatory cytokines (tumor necrosis factor alpha and interleukin‐6) in BAL for 30% both, P< 0.05. Animals that received Taxol ® alone had no appreciable effect on the parameters described above. These data suggests that microtubule destabilization may be involved in LPS‐induced lung injury in vivo . HL 58064; HL 60637