title: p38 Mitogen-activated protein kinase signaling regulates streptococcal M1 protein-induced neutrophil activation and lung injury.
abstract: M1 serotype of Streptococcus pyogenes can cause STSS and acute lung damage. Herein, the purpose was to define the role of p38 MAPK signaling in M1 protein-induced pulmonary injury. Male C57BL/6 mice were treated with specific p38 MAPK inhibitors (SB 239063 and SKF 86002) prior to M1 protein challenge. Edema, neutrophil infiltration, and CXC chemokines were determined in the lung, 4 h after M1 protein administration. Flow cytometry was used to determine Mac-1 expression. Phosphorylation and activity of p38 MAPK were determined by immunoprecipitation and Western blot. IVM was used to analyze leukocyte-endothelium interactions in the pulmonary microcirculation. M1 protein challenge increased phosphorylation and activity of p38 MAPK in the lung, which was inhibited by SB 239063 and SKF 86002. Inhibition of p38 MAPK activity decreased M1 protein-induced infiltration of neutrophils, edema, and CXC chemokine formation in the lung, as well as Mac-1 up-regulation on neutrophils. IVM showed that p38 MAPK inhibition reduced leukocyte rolling and adhesion in the pulmonary microvasculature of M1 protein-treated mice. Our results indicate that p38 MAPK signaling regulates neutrophil infiltration in acute lung injury induced by streptococcal M1 protein. Moreover, p38 MAPK activity controls CXC chemokine formation in the lung, as well as neutrophil expression of Mac-1 and recruitment in the pulmonary microvasculature. In conclusion, these findings suggest that targeting the p38 MAPK signaling pathway may open new opportunities to protect against lung injury in streptococcal infections.
authors.affiliation: Section for Surgery, Malmö University Hospital, Malmö, Sweden.
authors.forename: Songen
authors.initials: S
authors.lastname: Zhang
authors.forename: Milladur
authors.initials: M
authors.lastname: Rahman
authors.forename: Su
authors.initials: S
authors.lastname: Zhang
authors.forename: Yongzhi
authors.initials: Y
authors.lastname: Wang
authors.forename: Heiko
authors.initials: H
authors.lastname: Herwald
authors.forename: Bengt
authors.initials: B
authors.lastname: Jeppsson
authors.forename: Henrik
authors.initials: H
authors.lastname: Thorlacius
mesh_terms: D055371:Acute Lung Injury / Q000201:enzymology / Q000276:immunology / Q000382:microbiology; D000818:Animals; D000942:Antigens, Bacterial / Q000502:physiology*; D001425:Bacterial Outer Membrane Proteins / Q000502:physiology*; D002352:Carrier Proteins / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018375:Neutrophil Activation / Q000276:immunology*; D020556:Neutrophil Infiltration / Q000276:immunology; D013290:Streptococcal Infections / Q000276:immunology* / Q000378:metabolism; D013297:Streptococcus pyogenes / Q000276:immunology* / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology*
chemical_list: D000942:Antigens, Bacterial; D001425:Bacterial Outer Membrane Proteins; D002352:Carrier Proteins; C014689:streptococcal M protein; D048051:p38 Mitogen-Activated Protein Kinases