The role of Src kinase in inspiratory resistive breathing induced acute lung injury

Introduction: Inspiratory resistive breathing (IRB), a hallmark of obstructive pulmonary diseases, is characterized by large negative intrathoracic pressures and has been found to induce acute lung injury (ALI) in previously healthy rats. Src is a multifunctional kinase that is activated upon mechanical stress by phosphorylation. Aim: To investigate the role of Src in IRB-induced ALI. Methods: Anesthetized and tracheostomised rats were breathing spontaneously through a 2-way non rebreathing valve. The inspiratory port was connected to a resistance, setting peak tidal tracheal pressure at 50% of maximum (IRB). Quietly breathing animals served as controls. After 6 hours of IRB, the mechanics of the respiratory system were assessed with the forced oscillation technique. Bronchoalveolar lavage (BAL) was performed and total and differential cell count and total protein level were measured in BAL fluid. Activation of Src in the lung was detected by Western blot at 30min, 3 and 6 hours of IRB. Src inhibition was performed by an intraperitoneal injection of 1mg/kg of PP2, 30 min prior to IRB. Results: After 6 hours of IRB, increased tissue elasticity was measured, compared to control. Increased BAL cellularity was found, with raised numbers of both macrophages and neutrophils and total protein levels were elevated. Src activation was detected at 30 min of IRB. Inhibition of Src kinase attenuated the increase in tissue elasticity after 6 hours of IRB. Total cell count returned to control values with inhibition of Src kinase, with a decrease in both macrophage and neutrophil count. Total protein levels were not altered by Src inhibition. Conclusion: Src kinase activation partly mediates IRB induced ALI.