Intrapulmonary administration of a p38 mitogen activated protein kinase inhibitor partially prevents pulmonary inflammation

Gram-positive and gram-negative bacteria are common causative agents of respiratory tract infection. Lipopolysaccharide (LPS) is a component of the gram-negative cell wall and a strong inducer of inflammation. The main proinflammatory component of the gram-positive bacterial cell wall is lipoteichoic acid (LTA). The protein kinase p38 mitogen activated protein kinase (MAPK) plays an important role in the inflammatory process induced by these two bacterial structures. We here sought to establish the impact of local p38 MAPK inhibition on lung inflammatory responses induced by LPS and LTA. We investigated the effects of direct intrapulmonary delivery of a p38 MAPK inhibitor on local LPS and LTA induced airway inflammation in mice. In vitro, BIRB 796 reduced LPS induced p38 MAPK phosphorylation in alveolar macrophage and respiratory epithelial cell lines and diminished cytokine/chemokine release. In vivo, BIRB 796 circumvented p38 MAPK phosphorylation in both LPS and LTA induced inflammation. Cellular influx was not affected. Lung TNFα, IL-6, MIP-2 and LIX production was reduced in LPS induced inflammation but not in lung inflammation by LTA. BIRB 796 reduced total protein and IgM in bronchoalveolar lavage fluid after LTA instillation, while enhancing TATc and d-dimers in LPS- and LTA induced inflammation. These results taken together with earlier studies on systemic administration of p38 MAPK inhibitors in rodents and humans suggest that direct intrapulmonary delivery of a p38 MAPK inhibitor is less effective in inhibiting inflammation and is associated with unexpected procoagulant effects in the bronchoalveolar space