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


OBJECTIVE
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.


RESULTS
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.


CONCLUSIONS
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.
Center for Infection and Immunity Amsterdam, Academic Medical Center, Amsterdam, The Netherlands. a.j.hoogendijk@amc.uva.nl
Arie Johan
AJ
Hoogendijk
Sandra Sofia
SS
Pinhanços
Tom
T
van der Poll
Catharina Wilhelmina
CW
Wieland
D000818:Animals; D002460:Cell Line; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D005260:Female; D006801:Humans; D007075:Immunoglobulin M / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D016676:Macrophages, Alveolar / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D008297:Male; D051379:Mice; D009281:Naphthalenes / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects / Q000276:immunology; D011014:Pneumonia / Q000139:chemically induced / Q000201:enzymology / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011650:Pulmonary Alveoli / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D011720:Pyrazoles / Q000494:pharmacology*; D013682:Teichoic Acids / Q000633:toxicity; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D010671:Phenylurea Compounds
D016207:Cytokines; D007075:Immunoglobulin M; D008070:Lipopolysaccharides; D009281:Naphthalenes; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D013682:Teichoic Acids; D048051:p38 Mitogen-Activated Protein Kinases; C440499:lipopolysaccharide, Escherichia coli O111 B4; C009900:lipoteichoic acid; C452139:doramapimod; D010671:Phenylurea Compounds