Hyaluronan mediates airway hyperresponsiveness in oxidative lung injury.
Chlorine (Cl2) inhalation induces severe oxidative lung injury and airway hyperresponsiveness (AHR) that lead to asthmalike symptoms. When inhaled, Cl2 reacts with epithelial lining fluid, forming by-products that damage hyaluronan, a constituent of the extracellular matrix, causing the release of low-molecular-weight fragments (L-HA, <300 kDa), which initiate a series of proinflammatory events. Cl2 (400 ppm, 30 min) exposure to mice caused an increase of L-HA and its binding partner, inter-α-trypsin-inhibitor (IαI), in the bronchoalveolar lavage fluid. Airway resistance following methacholine challenge was increased 24 h post-Cl2 exposure. Intratracheal administration of high-molecular-weight hyaluronan (H-HA) or an antibody against IαI post-Cl2 exposure decreased AHR. Exposure of human airway smooth muscle (HASM) cells to Cl2 (100 ppm, 10 min) or incubation with Cl2-exposed H-HA (which fragments it to L-HA) increased membrane potential depolarization, intracellular Ca(2+), and RhoA activation. Inhibition of RhoA, chelation of intracellular Ca(2+), blockade of cation channels, as well as postexposure addition of H-HA, reversed membrane depolarization in HASM cells. We propose a paradigm in which oxidative lung injury generates reactive species and L-HA that activates RhoA and Ca(2+) channels of airway smooth muscle cells, increasing their contractility and thus causing AHR.
Department of Anesthesiology and Pulmonary Injury and Repair Center, School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama;
Ahmed
A
Lazrak
Department of Anesthesiology and Pulmonary Injury and Repair Center, School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama;
Judy
J
Creighton
Department of Anesthesiology and Pulmonary Injury and Repair Center, School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama;
Zhihong
Z
Yu
Department of Anesthesiology and Pulmonary Injury and Repair Center, School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama;
Svetlana
S
Komarova
Department of Anesthesiology and Pulmonary Injury and Repair Center, School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama;
Stephen F
SF
Doran
Department of Anesthesiology and Pulmonary Injury and Repair Center, School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama;
Saurabh
S
Aggarwal
Department of Anesthesiology, Columbia University, New York, New York; and.
Charles W
CW
Emala
Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina.
Vandy P
VP
Stober
Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina.
Carol S
CS
Trempus
Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina.
Stavros
S
Garantziotis
Department of Anesthesiology and Pulmonary Injury and Repair Center, School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama; sadis@uab.edu.
Sadis
S
Matalon
D000510:Alpha-Globulins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000276:immunology; D000818:Animals; D001249:Asthma / Q000188:drug therapy*; D016535:Bronchial Hyperreactivity / Q000188:drug therapy* / Q000276:immunology; D001985:Bronchial Provocation Tests; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers; D015220:Calcium Channels / Q000378:metabolism; D002478:Cells, Cultured; D002713:Chlorine / Q000633:toxicity; D004789:Enzyme Activation; D005109:Extracellular Matrix; D006820:Hyaluronic Acid / Q000627:therapeutic use*; D007249:Inflammation; D055370:Lung Injury / Q000188:drug therapy*; D008564:Membrane Potentials / Q000187:drug effects; D016210:Methacholine Chloride / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D009119:Muscle Contraction / Q000187:drug effects; D032389:Myocytes, Smooth Muscle; D018384:Oxidative Stress / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D017382:Reactive Oxygen Species / Q000378:metabolism; D014132:Trachea / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism; D020742:rhoA GTP-Binding Protein
D000510:Alpha-Globulins; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D017382:Reactive Oxygen Species; D016210:Methacholine Chloride; C011877:inter-alpha-inhibitor; D002713:Chlorine; D006820:Hyaluronic Acid; C526380:RhoA protein, mouse; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein; D002118:Calcium
calcium; chlorine; human airway smooth muscle; membrane potential; patch clamp