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Eur J Pharmacol. 2014 Jun 15;733:45-53. doi: 10.1016/j.ejphar.2014.03.029. Epub 2014 Apr 1.

Ras regulates alveolar macrophage formation of CXC chemokines and neutrophil activation in streptococcal M1 protein-induced lung injury.

Author information

1
Department of Clinical Sciences, Malmö, Section of Surgery and Experimental Infection Medicine, Skåne University Hospital, Lund University, Sweden.
2
Department of Clinical Sciences, Lund, Section for Clinical and Experimental Infection Medicine, Skåne University Hospital, Lund University, Sweden.
3
Department of Clinical Sciences, Malmö, Section of Surgery and Experimental Infection Medicine, Skåne University Hospital, Lund University, Sweden. Electronic address: henrik.thorlacius@med.lu.se.

Abstract

Streptococcal toxic shock syndrome (STSS) is associated with a high mortality rate. The M1 serotype of Streptococcus pyogenes is most frequently associated with STSS. Herein, we examined the role of Ras signaling in M1 protein-induced lung injury. Male C57BL/6 mice received the Ras inhibitor (farnesylthiosalicylic acid, FTS) prior to M1 protein challenge. Bronchoalveolar fluid and lung tissue were harvested for quantification of neutrophil recruitment, edema and CXC chemokine formation. Neutrophil expression of Mac-1 was quantified by use of flow cytometry. Quantitative RT-PCR was used to determine gene expression of CXC chemokines in alveolar macrophages. Administration of FTS reduced M1 protein-induced neutrophil recruitment, edema formation and tissue damage in the lung. M1 protein challenge increased Mac-1 expression on neutrophils and CXC chemokine levels in the lung. Inhibition of Ras activity decreased M1 protein-induced expression of Mac-1 on neutrophils and secretion of CXC chemokines in the lung. Moreover, FTS abolished M1 protein-provoked gene expression of CXC chemokines in alveolar macrophages. Ras inhibition decreased chemokine-mediated neutrophil migration in vitro. Taken together, our novel findings indicate that Ras signaling is a potent regulator of CXC chemokine formation and neutrophil infiltration in the lung. Thus, inhibition of Ras activity might be a useful way to antagonize streptococcal M1 protein-triggered acute lung injury.

KEYWORDS:

Adhesion; Leukocytes; Lung; Migration; Sepsis

PMID:
24704370
DOI:
10.1016/j.ejphar.2014.03.029
[Indexed for MEDLINE]
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