Regulation of Airway Smooth Muscle Contraction in Health and Disease

Asthma: A Loss of Post-natal Homeostatic Control of Airways Smooth Muscle With Regression Toward a Pre-natal State

“…Quite how ASM tone is regulated to prevent excessive narrowing is unknown (274,275). Possible mechanisms include (most likely first): a) Airways smooth muscle itself generates one or more autocrine negative feedback signals triggered by shortening (and lengthening) thus ensures ASM does not generate significant airways obstruction.…”

A New Pathway to Airway Relaxation: Targeting the “Other” Cyclase in Asthma

“…In contrast, in another study, both the NO donor NOC-5 and a stable cGMP analog inhibited serotonin-induced increases in the frequency of Ca 2+ oscillations, but not contractions, due to increased Ca 2+ sensitivity in mouse PCLSs (12). Because Ca 2+ signaling and sensitivity may both be dysregulated in asthma (reviewed in References 13 and 14), it will be important to separately define the capacities of different dilators to oppose each pathway. These results may then help elucidate the potential benefits of sGC agonists relative to SABAs and LABAs, both separately and in combination, in asthma.…”

“…The novel findings of efficacy and resistance to desensitization of sGC agonists require validation in a disease context to support clinical translation. Given the limited availability of isolated airways from subjects with asthma, human PCLSs could be treated in vitro with asthma-relevant inflammatory cytokines such as IL-1, tumor necrosis factor-α, and IL-13, an approach that has previously been shown to increase contractile responses and reduce responsiveness to β 2 -adrenoceptor agonists (reviewed in Reference 14). This would also complement the current study, in which overnight treatment with a high concentration of formoterol was used to cause β 2 -adrenoceptor desensitization (6).…”

“…Because sole SABA therapy loses favor in the face of accumulating evidence of a greater benefit from combined LABA/ICS over ICS alone at all stages of asthma (1, 2), the limitations of bronchodilator therapy with β 2 -adrenoceptor agonists still need to be addressed. Although a plethora of potential candidates, ranging from calcilytics and bitter-taste agonists to relaxin, have received significant support (14, 15), accumulating evidence indicates that targeting sGC also effectively opposes airway contraction (6, 7). Showing that sGC agonists are better bronchodilators than β 2 -adrenoceptor agonists in a disease context is the next step toward establishing a new pathway, traveling via sGC rather than the more familiar adenylate cyclase route.…”

The influence of alpha-tocopherol on the smooth muscle contractions

“…In fact, PGE 2 and PGI 2 can cause bronchodilation via DP 1 , EP 2 /EP 4 and IP 1 receptors, while PGD 2 , PGF 2α and TXA 2 can evoke bronchoconstriction by nonselective thromboxane and EP1/EP3 and FP receptors. 43,44 In respiratory diseases which involve bronchoconstriction like asthma or COPD, imbalance is evolved in production of prostanoids by inflammation. 45 The cervical ripening is crucial part of parturition.…”