Mechanical stimuli and IL-13 interact at integrin adhesion complexes to regulate expression of smooth muscle myosin heavy chain in airway smooth muscle tissue
Mechanical stimuli and IL-13 interact at integrin adhesion complexes to regulate expression of smooth muscle myosin heavy chain in airway smooth muscle tissue
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DOI：
10.1152/ajplung.00043.2011
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发表时间：
2011-09-01
影响因子：
4.9
通讯作者：
Gunst, Susan J.
中科院分区：
文献类型：
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作者：
Desai, Leena P.;Wu, Yidi;Gunst, Susan J.
Desai LP，Wu Y，Tepper RS，Gunst SJ.机械刺激和IL-13在整合素粘附复合物中相互作用以调节气道平滑肌组织中平滑肌肌球蛋白重链的表达。美国生理学杂志肺细胞分子生理学301：L275-L284，2011年。首次发表于2011年6月3日; doi：10.1152/ajplung.00043.2011。在生理和病理生理条件下，气道平滑肌表型可响应于外部刺激而被调节。通过从犬气管平滑肌组织的末端悬置0.5或1g的重量，将称重的组织孵育6 h，然后测量表型标记蛋白平滑肌肌球蛋白重链（SmMHC）的表达，在体外评估机械力对气道平滑肌表型的影响。与低负荷孵育相比，高负荷孵育组织显著增加SmMHC的表达。在高负荷下孵育组织也降低了PKB/Akt的活化，如其在Ser 473的磷酸化所示。Akt或磷脂酰肌醇-3，4，5三磷酸激酶的抑制在低负荷下增加组织中SmMHC的表达，但在高负荷下不影响SmMHC的表达。IL-13诱导Akt激活的显着增加，并抑制SmMHC蛋白的表达在低和高负荷。通过在肌肉组织中表达阻止整合素结合IPP复合物（ILK/PINCH/α-parvin）的膜定位的PINCH（LIM 1 -2）片段，并且还通过表达抑制内源性ILK活性的无活性整合素连接的激酶突变体（ILK S343 A），来评估整合素信号传导在机械转导中的作用。两种突变体在低负荷下均抑制Akt活化并增加SmMHC蛋白的表达，但在高负荷下无影响。这些结果表明，机械应力和IL-13都通过整合素介导的信号通路，以相反的方式调节表型标记蛋白在完整的气道平滑肌组织中的表达。机械应力对收缩蛋白表达的刺激作用与IL-13介导的收缩蛋白表达的抑制作用相反;因此，机械应力的施加可能抑制炎症介质诱导的气道平滑肌表型的变化。
Desai LP, Wu Y, Tepper RS, Gunst SJ. Mechanical stimuli and IL-13 interact at integrin adhesion complexes to regulate expression of smooth muscle myosin heavy chain in airway smooth muscle tissue. Am J Physiol Lung Cell Mol Physiol 301: L275-L284, 2011. First published June 3, 2011; doi:10.1152/ajplung.00043.2011.-Airway smooth muscle phenotype may be modulated in response to external stimuli under physiological and pathophysiological conditions. The effect of mechanical forces on airway smooth muscle phenotype were evaluated in vitro by suspending weights of 0.5 or 1 g from the ends of canine tracheal smooth muscle tissues, incubating the weighted tissues for 6 h, and then measuring the expression of the phenotypic marker protein, smooth muscle myosin heavy chain (SmMHC). Incubation of the tissues at a high load significantly increased expression of SmMHC compared with incubation at low load. Incubation of the tissues at a high load also decreased activation of PKB/Akt, as indicated by its phosphorylation at Ser 473. Inhibition of Akt or phosphatidylinositol-3,4,5 triphosphate-kinase increased SmMHC expression in tissues at low load but did not affect SmMHC expression at high load. IL-13 induced a significant increase in Akt activation and suppressed the expression of SmMHC protein at both low and high loads. The role of integrin signaling in mechanotransduction was evaluated by expressing a PINCH (LIM1-2) fragment in the muscle tissues that prevents the membrane localization of the integrin-binding IPP complex (ILK/PINCH/alpha-parvin), and also by expressing an inactive integrin-linked kinase mutant (ILK S343A) that inhibits endogenous ILK activity. Both mutants inhibited Akt activation and increased expression of SmMHC protein at low load but had no effect at high load. These results suggest that mechanical stress and IL-13 both act through an integrin-mediated signaling pathway to oppositely regulate the expression of phenotypic marker proteins in intact airway smooth muscle tissues. The stimulatory effects of mechanical stress on contractile protein expression oppose the suppression of contractile protein expression mediated by IL-13; thus the imposition of mechanical strain may inhibit changes in airway smooth muscle phenotype induced by inflammatory mediators.