P38 Inhibition Ameliorates Inspiratory Resistive Breathing-Induced Pulmonary Inflammation.

Abstract

Inspiratory resistive breathing (IRB), a hallmark of obstructive airway diseases, is associated with strenuous contractions of the inspiratory muscles and increased negative intrathoracic pressures that act as an injurious stimulus to the lung. We have shown that IRB induces pulmonary inflammation in healthy animals. p38 kinase is activated in the lung under stress. We hypothesized that p38 is activated during IRB and contributes to IRB-induced pulmonary inflammation. Anesthetized, tracheostomized rats breathed spontaneously through a two-way valve. Resistance was connected to the inspiratory port to provoke a peak tidal inspiratory pressure 50% of maximum. Following 3 and 6h of IRB, respiratory system mechanics were measured and bronchoalveolar lavage (BAL) was performed. Phosphorylated p38, TNF-α, and MIP-2α were detected in lung tissue. Lung injury was estimated histologically. SB203580 (p38 inhibitor) was administered prior to IRB (1mgkg-1). Six hours of IRB increased phosphorylated p38 in the lung, compared with quietly breathing controls (p = 0.001). Six hours of IRB increased the numbers of macrophages and neutrophils (p = 0.01 and p = 0.005) in BAL fluid. BAL protein levels and lung elasticity increased after both 3 and 6h IRB. TNF-α and MIP-2α increased after 6h of IRB (p = 0.01 and p < 0.001, respectively). Increased lung injury score was detected at 6h IRB. SB203580 administration blocked the increase of neutrophils and macrophages at 6h IRB (p = 0.01 and p = 0.005 to 6h IRB) but not the increase in BAL protein and elasticity. TNF-α, MIP-2α, and injury score at 6h IRB returned to control. p38 activation contributes to IRB-induced pulmonary inflammation.