Alveolar macrophage inducible nitric oxide synthase-dependent pulmonary microvascular endothelial cell septic barrier dysfunction |
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| Affiliation: | 1. Department of Chemistry and Biochemistry, Faculty of Science I, Lebanese University, Hadath, Beirut, Lebanon;2. Department of Chemistry and Biotechnology, Faculty of Science, Engineering and Technology, Swinburne University of Technology, Melbourne, Australia;3. Howard Hughes Medical Institute, California Institute of Technology, Pasadena, California 91125;4. University of Queensland, Brisbane, Queensland 4072, Australia;1. Departments of Geriatrics, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, PR China;2. Departments of Nephrology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, PR China;3. Department of Nephrology, Benxi Center Hospital, China Medical University, Benxi, Liaoning 117000, PR China;1. Institute of Functional and Applied Anatomy, Hannover Medical School, Carl-Neuberg-Straße 1, 30625 Hannover, Germany;2. Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Hannover, Germany;3. REBIRTH Cluster of Excellence, Hannover, Germany;4. Institute of Laboratory Animal Science, Hannover Medical School, Carl-Neuberg-Straße 1, 30625 Hannover, Germany;1. Department of Molecular & Integrative Physiology, University of Michigan Medical School, 7744 Medical Science Building II, 1301 E. Catherine, Ann Arbor, MI 48109, United States;2. Department of Medicine, University of Michigan Medical School, 7744 Medical Science Building II, 1301 E. Catherine, Ann Arbor, MI 48109, United States;3. Ann Arbor Health System VA Medical Center, United States;1. Department of Spinal Surgery, Jining No. 1 People''s Hospital, Jining, Shandong, 272011, PR China;2. Department of Urology Surgery, Jining No. 1 People''s Hospital, Jining, Shandong, 272011, PR China;1. Department of Computer Science and Engineering, Netaji Subhash Engineering College, Kolkata 700152, India;2. Department of Information Technology, Jadavpur University, Kolkata, India;3. Machine Intelligence Unit, Indian Statistical Institute, Kolkata 700108, India |
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| Abstract: | ![]()
Inducible nitric oxide (NO) synthase (iNOS) from neutrophils and alveolar macrophages (AM) contributes to the pathophysiology of murine septic acute lung injury (ALI). It is not known if AM iNOS has a direct effect on septic pulmonary microvascular endothelial cell (PMVEC) permeability. We hypothesized that AM iNOS mediates PMVEC permeability in vitro under septic conditions through NO and peroxynitrite. 100,000 confluent PMVEC on cell-culture inserts were co-incubated with iNOS+/+ vs. iNOS−/− AM, in various ratios of AM to PMVEC. PMVEC injury was assessed by trans-PMVEC Evans Blue-labelled albumin flux in the presence or absence of cytomix (equimolar TNF-α, IL-1β and IFN-γ). Cytomix stimulation dose-dependently increased trans-PMVEC EB-albumin flux, which was exaggerated (1.4 ± 0.1% vs. 0.4 ± 0.1% in unstimulated PMVEC, p < 0.05) in the presence of iNOS+/+, but not iNOS−/−, AM in the upper compartment. Similarly, iNOS+/+, but not iNOS−/−, AM in the lower compartment also enhanced septic trans-PMVEC albumin leak. The mechanism of iNOS-dependent septic PMVEC permeability was pursued through pharmacologic studies with inhibitors of NOS, and scavengers of NO, superoxide, and peroxynitrite, and treatment of PMVEC with the NO donor, DETA-NONOate. Septic iNOS+/+ AM-dependent trans-PMVEC albumin leak was significantly attenuated by pharmacologic iNOS inhibition (L-NAME and 1400W), and scavenging of either NO (oxyhemoglobin), superoxide (PEG-SOD), or peroxynitrite (FeTPPS). Exogenous NO (DETA-NONOate) had no effect on PMVEC permeability. These data are consistent with a direct role of AM iNOS in septic PMVEC barrier dysfunction, which is likely mediated, in part, through peroxynitrite. |
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