title: Lipopolysaccharide Induces Alveolar Macrophage Necrosis via CD14 and the P2X7 Receptor Leading to Interleukin-1α Release.
abstract: Acute lung injury (ALI) remains a serious health issue with little improvement in our understanding of the pathophysiology and therapeutic approaches. We investigated the mechanism that lipopolysaccharide (LPS) induces early neutrophil recruitment to lungs and increases pulmonary vascular permeability during ALI. Intratracheal LPS induced release of pro-interleukin-1α (IL-1α) from necrotic alveolar macrophages (AM), which activated endothelial cells (EC) to induce vascular leakage via loss of vascular endothelial (VE)-cadherin. LPS triggered the AM purinergic receptor P2X7(R) to induce Ca(2+) influx and ATP depletion, which led to necrosis. P2X7R deficiency significantly reduced necrotic death of AM and release of pro-IL-1α into the lung. CD14 was required for LPS binding to P2X7R, as CD14 neutralization significantly diminished LPS induced necrotic death of AM and pro-IL-1α release. These results demonstrate a key role for pro-IL-1α from necrotic alveolar macrophages in LPS-mediated ALI, as a critical initiator of increased vascular permeability and early neutrophil infiltration.
authors: Departments of Biomedical Sciences, Medicine and Pediatrics, Divisions of Infectious Diseases and Immunology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors: Jargalsaikhan
authors: J
authors: Dagvadorj
authors: Departments of Biomedical Sciences, Medicine and Pediatrics, Divisions of Infectious Diseases and Immunology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Infectious and Immunologic Diseases Research Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors: Kenichi
authors: K
authors: Shimada
authors: Departments of Biomedical Sciences, Medicine and Pediatrics, Divisions of Infectious Diseases and Immunology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Infectious and Immunologic Diseases Research Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors: Shuang
authors: S
authors: Chen
authors: Infectious and Immunologic Diseases Research Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Division of Pulmonary and Critical Care Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors: Heather D
authors: HD
authors: Jones
authors: Departments of Biomedical Sciences, Medicine and Pediatrics, Divisions of Infectious Diseases and Immunology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors: Gantsetseg
authors: G
authors: Tumurkhuu
authors: Departments of Biomedical Sciences, Medicine and Pediatrics, Divisions of Infectious Diseases and Immunology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors: Wenxuan
authors: W
authors: Zhang
authors: Confocal Core, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors: Kolja A
authors: KA
authors: Wawrowsky
authors: Departments of Biomedical Sciences, Medicine and Pediatrics, Divisions of Infectious Diseases and Immunology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Infectious and Immunologic Diseases Research Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors: Timothy R
authors: TR
authors: Crother
authors: Departments of Biomedical Sciences, Medicine and Pediatrics, Divisions of Infectious Diseases and Immunology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Infectious and Immunologic Diseases Research Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; David Geffen School of Medicine, UCLA, Los Angeles, CA 90048, USA. Electronic address: moshe.arditi@cshs.org.
authors: Moshe
authors: M
authors: Arditi
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000276:immunology / Q000473:pathology; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D015820:Cadherins / Q000235:genetics / Q000276:immunology; D002118:Calcium / Q000378:metabolism; D002199:Capillary Permeability / Q000276:immunology; D042783:Endothelial Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D053582:Interleukin-1alpha / Q000235:genetics / Q000276:immunology*; D007442:Intubation, Intratracheal; D018950:Lipopolysaccharide Receptors / Q000235:genetics / Q000276:immunology*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D016676:Macrophages, Alveolar / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009336:Necrosis / Q000139:chemically induced / Q000276:immunology / Q000473:pathology; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D011498:Protein Precursors / Q000235:genetics / Q000276:immunology; D058486:Receptors, Purinergic P2X7 / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction
chemical_list: D015820:Cadherins; D053582:Interleukin-1alpha; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D011498:Protein Precursors; D058486:Receptors, Purinergic P2X7; D000255:Adenosine Triphosphate; D002118:Calcium