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However, the mechanisms underlying the protective effect of CO\u2010releasing molecule\u20102 (CORM\u20102)\u2010induced HO\u20101 expression against TNF\u2010\u03b1\u2010induced inflammatory responses in human pulmonary alveolar epithelial cells (HPAEpiCs) remain unknown.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>CORM\u20102\u2010induced HO\u20101 protein and mRNA expression, and signalling pathways were determined by Western blot and real\u2010time PCR, coupled with respective pharmacological inhibitors or transfection with siRNAs. The effect of CORM\u20102 on TNF\u2010\u03b1\u2010induced increase in leukocyte counts in BAL fluid and VCAM\u20101 expression in lung was determined by cell counting and Western blot analysis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>CORM\u20102 attenuated the TNF\u2010\u03b1\u2010induced pulmonary haematoma, VCAM\u20101 expression and increase in leukocytes through an up\u2010regulation of HO\u20101 in mice; this effect of CORM\u20102 was reversed by the HO\u20101 inhibitor zinc protoporphyrin IX. Furthermore, CORM\u20102 increased HO\u20101 protein and mRNA expression as well as the phosphorylation of PYK2, PKC\u03b1 and ERK1\/2 (p44\/p42 MAPK) in HPAEpiCs; these effects were attenuated by their respective pharmacological inhibitors or transfection with siRNAs. Inhibition of PKC\u03b1 by G\u00f66976 or G\u00f66983 attenuated CORM\u20102\u2010induced stimulation of PKC\u03b1 and ERK1\/2 phosphorylation but had no effect on PYK2 phosphorylation. Moreover, inhibition of PYK2 by PF431396 reduced the phosphorylation of all three protein kinases. Finally, PYK2\/PKC\u03b1\/ERK1\/2\u2010mediated stimulation of activator protein 1 was shown to play a key role in CORM\u20102\u2010induced HO\u20101 expression <jats:italic>via<\/jats:italic> an up\u2010regulation of c\u2010Fos mRNA.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>CORM\u20102 activates a PYK2\/PKC\u03b1\/ERK1\/2\/AP\u20101 pathway leading to HO\u20101 expression in HPAEpiCs. This HO\u20101\/CO system might have potential as a therapeutic target in pulmonary inflammation.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.14094","type":"journal-article","created":{"date-parts":[[2017,11,15]],"date-time":"2017-11-15T11:39:33Z","timestamp":1510745973000},"page":"456-468","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Up\u2010regulation of PYK2\/PKC\u03b1\u2010dependent haem oxygenase\u20101 by CO\u2010releasing molecule\u20102 attenuates TNF\u2010\u03b1\u2010induced lung inflammation"],"prefix":"10.1111","volume":"175","author":[{"given":"Chih\u2010Chung","family":"Lin","sequence":"first","affiliation":[{"name":"Department of Anaesthetics Chang Gung Memorial Hospital at Linkuo and Chang Gung University  Tao\u2010Yuan Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu\u2010Ching","family":"Chiang","sequence":"additional","affiliation":[{"name":"Department of Physiology and 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