PURPOSE: Previous work has shown that inducible nitric oxide synthase (iNOS) derived from inflammatory cells plays a particularly important role in the development of high-protein pulmonary edema and increased oxidative stress in sepsis-induced acute lung injury (ALI). Interestingly, iNOS-/- animals show increased pulmonary polymorphonuclear leukocyte (PMN) infiltration despite decreased lung injury. The purpose of this study was to test the hypothesis that iNOS reduces pulmonary production of CXC chemokines and increases surface expression of adhesion molecules on PMN.
METHODS: Experiments were performed using iNOS+/+ and iNOS-/- C57BL/6 mice. Sepsis was induced via cecal ligation and perforation (CLP), the lungs were removed and homogenized for analysis of the CXC chemokine macrophage inflammatory protein-2 (MIP-2). Alveolar macrophages (AM) were cultured, stimulated with LPS+IFN-[gamma] and the culture medium was analyzed for MIP-2 production. Surface expression of CD11b and CD62L was measured via flow cytometry in bone marrow PMN after LPS+IFN-[gamma] stimulation.
RESULTS: MIP-2 levels in lung homogenate were increased in septic mice vs control and were significantly lower in septic iNOS+/+ vs iNOS-/- mice (35.8 [+ or -] 12.3 vs 67.4 [+ or -] 14.2 ng/mL). AM MIP-2 production increased following LPS +IFN-[gamma] stimulation but there was no difference between iNOS+/+ and iNOS-/- AM. Bone marrow PMN stimulated with LPS+IFN-[gamma] showed increased expression of CD11b and decreased expression of CD62L vs control but there was no difference between iNOS+/+ and iNOS+/+ PMN.
CONCLUSION: iNOS inhibits septic pulmonary, but not AM production of MIP-2. PMN iNOS has no apparent effect septic PMN surface expression of CD11b and CD62L on PMN.
CLINICAL IMPLICATIONS: A better understanding of the mechanisms by which iNOS affects PMN infiltration and sequestration may lead to new therapeutic options for patients with ALI.
DISCLOSURE: Cedrin Law, None.
Cedrin S. Law BSc * Ravi Taneja MD Lefeng Wang PhD El-Bdaoui Haddad PhD George De Sanctis PhD David G. McCormack MD Sanjay Mehta MD Lawson Health Research Institute, London, ON, Canada
COPYRIGHT 2005 American College of Chest Physicians
COPYRIGHT 2005 Gale Group
Contact
Home
A
Arthritis