Differential effects of the Src family tyrosine kinases Yes and Fyn on lipopolysaccharide-induced lung injury in mice.

Abstract

Endothelial cell apoptosis is an early event in the development of acute lung injury (ALI). We have previously found that the Src family tyrosine kinase (STK) Yes activates caspase-3, whereas the STK Fyn inhibits caspase-3 activation in cultured pulmonary endothelial cells. We hypothesized that deficiency in Yes or Fyn in mice would have differential effects on lipopolysaccharide (LPS)-induced ALI. Mice were treated with LPS (10 mg/kg ip) for 24 h. Histological evidence of lung injury was greater in LPS-treated wild-type mice than in vehicle-treated wild-type mice, and the LPS-induced histological evidence of lung injury was attenuated in yes-/- mice and enhanced in fyn-/- mice. In wild-type or fyn-/- mice, LPS resulted in greater lung wet-to-dry weight ratios than in controls, whereas in yes-/- mice lung, wet-to-dry weight was similar between LPS and controls. LPS-exposed fyn-/- mice had greater respiratory system resistance and lower respiratory system compliance than did LPS-exposed wild-type mice. TUNEL positive cells in the lung following LPS treatment were greater in the fyn-/- mice and lower in the yes-/- mice compared with that in the wild-type mice. Following LPS treatment lung protein levels of PECAM-1 were lower in fyn-/- mice than in controls or yes-/- mice. LPS treatment increased cleaved caspase-3 protein levels in wild-type mice, whereas LPS-induced caspase-3 activation was attenuated in yes-/- mice and enhanced in fyn-/- mice. These results indicate that LPS-induced ALI is positively mediated via Yes-related mechanisms and negatively mediated by Fyn-related mechanisms.