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When inhaled, Cl<jats:sub>2<\/jats:sub> 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, &lt;300 kDa), which initiate a series of proinflammatory events. Cl<jats:sub>2<\/jats:sub> (400 ppm, 30 min) exposure to mice caused an increase of L-HA and its binding partner, inter-\u03b1-trypsin-inhibitor (I\u03b1I), in the bronchoalveolar lavage fluid. Airway resistance following methacholine challenge was increased 24 h post-Cl<jats:sub>2<\/jats:sub> exposure. Intratracheal administration of high-molecular-weight hyaluronan (H-HA) or an antibody against I\u03b1I post-Cl<jats:sub>2<\/jats:sub> exposure decreased AHR. Exposure of human airway smooth muscle (HASM) cells to Cl<jats:sub>2<\/jats:sub> (100 ppm, 10 min) or incubation with Cl<jats:sub>2<\/jats:sub>-exposed H-HA (which fragments it to L-HA) increased membrane potential depolarization, intracellular Ca<jats:sup>2+<\/jats:sup>, and RhoA activation. Inhibition of RhoA, chelation of intracellular Ca<jats:sup>2+<\/jats:sup>, 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<jats:sup>2+<\/jats:sup> channels of airway smooth muscle cells, increasing their contractility and thus causing AHR. <\/jats:p>","DOI":"10.1152\/ajplung.00377.2014","type":"journal-article","created":{"date-parts":[[2015,3,6]],"date-time":"2015-03-06T22:13:07Z","timestamp":1425679987000},"page":"L891-L903","source":"Crossref","is-referenced-by-count":63,"title":["Hyaluronan mediates airway hyperresponsiveness in oxidative lung injury"],"prefix":"10.1152","volume":"308","author":[{"given":"Ahmed","family":"Lazrak","sequence":"first","affiliation":[{"name":"Department of Anesthesiology and Pulmonary Injury and Repair Center, School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judy","family":"Creighton","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and 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