Ras regulates alveolar macrophage formation of CXC chemokines and neutrophil activation in streptococcal M1 protein-induced lung injury.
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.
Department of Clinical Sciences, Malmö, Section of Surgery and Experimental Infection Medicine, Skåne University Hospital, Lund University, Sweden.
Songen
S
Zhang
Department of Clinical Sciences, Malmö, Section of Surgery and Experimental Infection Medicine, Skåne University Hospital, Lund University, Sweden.
Rundk
R
Hwaiz
Department of Clinical Sciences, Malmö, Section of Surgery and Experimental Infection Medicine, Skåne University Hospital, Lund University, Sweden.
Milladur
M
Rahman
Department of Clinical Sciences, Lund, Section for Clinical and Experimental Infection Medicine, Skåne University Hospital, Lund University, Sweden.
Heiko
H
Herwald
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.
Henrik
H
Thorlacius
D000818:Animals; D000942:Antigens, Bacterial / Q000633:toxicity*; D001425:Bacterial Outer Membrane Proteins / Q000633:toxicity*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology / Q000276:immunology; D002352:Carrier Proteins / Q000633:toxicity*; D019743:Chemokines, CXC / Q000096:biosynthesis / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005204:Farnesol / Q000031:analogs & derivatives / Q000494:pharmacology; D005434:Flow Cytometry; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D055370:Lung Injury / Q000139:chemically induced* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016676:Macrophages, Alveolar / Q000276:immunology* / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D020556:Neutrophil Infiltration / Q000187:drug effects / Q000276:immunology; D011654:Pulmonary Edema / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D012459:Salicylates / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D018631:ras Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*
D000942:Antigens, Bacterial; D001425:Bacterial Outer Membrane Proteins; D002352:Carrier Proteins; D019743:Chemokines, CXC; D012459:Salicylates; C093323:farnesylthiosalicylic acid; C014689:streptococcal M protein; D005204:Farnesol; D018631:ras Proteins
Adhesion; Leukocytes; Lung; Migration; Sepsis