title: A Critical Role for P2X7 Receptor-Induced VCAM-1 Shedding and Neutrophil Infiltration during Acute Lung Injury.
abstract: Pulmonary neutrophils are the initial inflammatory cells that are recruited during lung injury and are crucial for innate immunity. However, pathological recruitment of neutrophils results in lung injury. The objective of this study is to determine whether the novel neutrophil chemoattractant, soluble VCAM-1 (sVCAM-1), recruits pathological levels of neutrophils to injury sites and amplifies lung inflammation during acute lung injury. The mice with P2X7 receptor deficiency, or treated with a P2X7 receptor inhibitor or anti-VCAM-1 Abs, were subjected to a clinically relevant two-hit LPS and mechanical ventilation-induced acute lung injury. Neutrophil infiltration and lung inflammation were measured. Neutrophil chemotactic activities were determined by a chemotaxis assay. VCAM-1 shedding and signaling pathways were assessed in isolated lung epithelial cells. Ab neutralization of sVCAM-1 or deficiency or antagonism of P2X7R reduced neutrophil infiltration and proinflammatory cytokine levels. The ligands for sVCAM-1 were increased during acute lung injury. sVCAM-1 had neutrophil chemotactic activities and activated alveolar macrophages. VCAM-1 is released into the alveolar airspace from alveolar epithelial type I cells through P2X7 receptor-mediated activation of the metalloproteinase ADAM-17. In conclusion, sVCAM-1 is a novel chemoattractant for neutrophils and an activator for alveolar macrophages. Targeting sVCAM-1 provides a therapeutic intervention that could block pathological neutrophil recruitment, without interfering with the physiological recruitment of neutrophils, thus avoiding the impairment of host defenses.
authors: Lundberg-Kienlen Lung Biology and Toxicology Laboratory, Department of Physiological Sciences, Oklahoma State University, Stillwater, OK 74078;
authors: Amarjit
authors: 0000-0002-3777-0338
authors: A
authors: Mishra
authors: Lundberg-Kienlen Lung Biology and Toxicology Laboratory, Department of Physiological Sciences, Oklahoma State University, Stillwater, OK 74078; Oklahoma Center for Respiratory and Infectious Diseases, Oklahoma State University, Stillwater, OK 74078;
authors: Yujie
authors: Y
authors: Guo
authors: Lundberg-Kienlen Lung Biology and Toxicology Laboratory, Department of Physiological Sciences, Oklahoma State University, Stillwater, OK 74078;
authors: Li
authors: L
authors: Zhang
authors: Lundberg-Kienlen Lung Biology and Toxicology Laboratory, Department of Physiological Sciences, Oklahoma State University, Stillwater, OK 74078; Oklahoma Center for Respiratory and Infectious Diseases, Oklahoma State University, Stillwater, OK 74078;
authors: Sunil
authors: 0000-0001-5007-8795
authors: S
authors: More
authors: Lundberg-Kienlen Lung Biology and Toxicology Laboratory, Department of Physiological Sciences, Oklahoma State University, Stillwater, OK 74078;
authors: Tingting
authors: T
authors: Weng
authors: Lundberg-Kienlen Lung Biology and Toxicology Laboratory, Department of Physiological Sciences, Oklahoma State University, Stillwater, OK 74078;
authors: Narendranath Reddy
authors: NR
authors: Chintagari
authors: Lundberg-Kienlen Lung Biology and Toxicology Laboratory, Department of Physiological Sciences, Oklahoma State University, Stillwater, OK 74078; Oklahoma Center for Respiratory and Infectious Diseases, Oklahoma State University, Stillwater, OK 74078;
authors: Chaoqun
authors: C
authors: Huang
authors: Lundberg-Kienlen Lung Biology and Toxicology Laboratory, Department of Physiological Sciences, Oklahoma State University, Stillwater, OK 74078; Oklahoma Center for Respiratory and Infectious Diseases, Oklahoma State University, Stillwater, OK 74078;
authors: Yurong
authors: Y
authors: Liang
authors: Lundberg-Kienlen Lung Biology and Toxicology Laboratory, Department of Physiological Sciences, Oklahoma State University, Stillwater, OK 74078; Oklahoma Center for Respiratory and Infectious Diseases, Oklahoma State University, Stillwater, OK 74078;
authors: Samuel
authors: 0000-0002-5746-280X
authors: S
authors: Pushparaj
authors: Shenzhen Key Laboratory of Microbial Genetic Engineering, College of Life Sciences, Shenzhen University, Shenzhen, Guangdong 518060, China; and.
authors: Deming
authors: 0000-0002-3312-841X
authors: D
authors: Gou
authors: Oklahoma Center for Respiratory and Infectious Diseases, Oklahoma State University, Stillwater, OK 74078; Department of Pathobiology, Oklahoma State University, Stillwater, OK 74078.
authors: Melanie
authors: M
authors: Breshears
authors: Lundberg-Kienlen Lung Biology and Toxicology Laboratory, Department of Physiological Sciences, Oklahoma State University, Stillwater, OK 74078; Oklahoma Center for Respiratory and Infectious Diseases, Oklahoma State University, Stillwater, OK 74078; lin.liu@okstate.edu.
authors: Lin
authors: 0000-0002-4811-4897
authors: L
authors: Liu
mesh_terms: D055371:Acute Lung Injury / Q000276:immunology* / Q000473:pathology; D000818:Animals; D004195:Disease Models, Animal; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology* / Q000473:pathology; D058486:Receptors, Purinergic P2X7 / Q000172:deficiency / Q000276:immunology* / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000276:immunology*
chemical_list: D058486:Receptors, Purinergic P2X7; D019010:Vascular Cell Adhesion Molecule-1