title: Rac1 signaling regulates sepsis-induced pathologic inflammation in the lung via attenuation of Mac-1 expression and CXC chemokine formation.
abstract: Excessive neutrophil recruitment is a major feature in septic lung damage although the signaling mechanisms behind pulmonary infiltration of neutrophils in sepsis remain elusive. In the present study, we hypothesized that Rac1 might play an important role in pulmonary neutrophil accumulation and tissue injury in abdominal sepsis. Male C57BL/6 mice were treated with Rac1 inhibitor NSC23766 (5 mg/kg) before cecal ligation and puncture (CLP). Bronchoalveolar lavage fluid and lung tissue were collected for the quantification of neutrophil recruitment and edema and CXC chemokine formation. Blood was collected for the determination of Mac-1 on neutrophils and proinflammatory compounds in plasma. Gene expression of CXC chemokines and tumor necrosis factor alpha was determined by quantitative reverse transcription-polymerase chain reaction in alveolar macrophages. Rac1 activity was increased in lungs from septic animals, and NSC23766 significantly decreased pulmonary activity of Rac1 induced by CLP. Administration of NSC23766 markedly reduced CLP-triggered neutrophil infiltration, edema formation, and tissue damage in the lung. Inhibition of Rac1 decreased CLP-induced neutrophil expression of Mac-1 and pulmonary formation of CXC chemokines. Moreover, NSC23766 abolished the sepsis-evoked elevation of messenger RNA levels of CXC chemokines and tumor necrosis factor alpha in alveolar macrophages. Rac1 inhibition decreased the CLP-induced increase in plasma levels of high mobility group protein B1 and interleukin 6, indicating a role of Rac1 in systemic inflammation. In conclusion, our results demonstrate that Rac1 signaling plays a key role in regulating pulmonary infiltration of neutrophils and tissue injury via regulation of chemokine production in the lung and Mac-1 expression on neutrophils in abdominal sepsis. Thus, targeting Rac1 activity might be a useful strategy to protect the lung in abdominal sepsis.
authors.affiliation: Section of Surgery, Department of Clinical Sciences, Lund University, Malmö, Sweden.
authors.forename: Rundk
authors.initials: R
authors.lastname: Hwaiz
authors.forename: Zirak
authors.initials: Z
authors.lastname: Hasan
authors.forename: Milladur
authors.initials: M
authors.lastname: Rahman
authors.forename: Su
authors.initials: S
authors.lastname: Zhang
authors.forename: Karzan
authors.initials: K
authors.lastname: Palani
authors.forename: Ingvar
authors.initials: I
authors.lastname: Syk
authors.forename: Bengt
authors.initials: B
authors.lastname: Jeppsson
authors.forename: Henrik
authors.initials: H
authors.lastname: Thorlacius
mesh_terms: D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D002432:Cecum / Q000293:injuries; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D019743:Chemokines, CXC / Q000378:metabolism*; D004195:Disease Models, Animal; D024243:HMGB1 Protein / Q000378:metabolism; D066298:In Vitro Techniques; D008026:Ligation / Q000009:adverse effects; D016177:Macrophage-1 Antigen / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009479:Neuropeptides / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000502:physiology*; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011014:Pneumonia / Q000382:microbiology* / Q000473:pathology / Q000503:physiopathology*; D011677:Punctures / Q000009:adverse effects; D011743:Pyrimidines / Q000494:pharmacology; D018805:Sepsis / Q000150:complications* / Q000209:etiology; D015398:Signal Transduction / Q000502:physiology*; D020744:rac GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000502:physiology*; D020830:rac1 GTP-Binding Protein
chemical_list: D000634:Aminoquinolines; D019743:Chemokines, CXC; D024243:HMGB1 Protein; D016177:Macrophage-1 Antigen; C487513:NSC 23766; D009479:Neuropeptides; D011743:Pyrimidines; C484602:Rac1 protein, mouse; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein
keywords: Adhesion; Inflammation; Leukocytes; Migration and platelets