Mechanisms of intrinsic force in small human airways

Abstract

We quantified the magnitude and investigated mechanisms regulating intrinsic force (IF) in human airway smooth muscle (hASM). IF was identified by reducing extracellular calcium (Ca2+) concentration to nominally zero in freshly isolated isometrically mounted 2 mm human bronchi. Our results show: (1) the magnitude of IF is ~ 50% of the maximal total force elicited by acetylcholine (10-5 M) and is epithelial-independent, (2) IF can also be revealed by β-adrenergic activation (isoproterenol), non-specific cationic channel blockade (La3+) or L-type voltage gated Ca2+ channel blockade (nifedipine), (3) atropine, indomethacin, AA– 861, or pyrilamine did not affect IF, (4) IF was reduced by the intracellular Ca2+ ([Ca2+]i) chelating agent BAPTA-AM, (5) ω-conotoxin had no effect on IF. In studies in cultured hASM cells nominally zero Ca2+ buffer and BAPTA-AM reduced [Ca2+]i but isoproterenol and nifedipine did not. Taken together these results indicate that rapid reduction of [Ca2+]i reveals a permissive relationship between extracellular Ca2+, [Ca2+]i and IF. However IF can be dissipated by mechanisms effecting Ca2+ sensitivity. We speculate that an increase of IF, a fundamental property of ASM, could be related to human airway clinical hyperresponsiveness and must be accounted for in in vitro studies of hASM.

Mechanisms of Cigarette Smoke Effects on Human Airway Smooth Muscle

“…[Ca 2+ ] i regulation is central to ASM intrinsic force [24], as well as agonist-elicited force generation. Moreover, [Ca 2+ ] i regulation is an early signal in cellular proliferation.…”

“…Recently, several studies suggest that Ca 2+ homeostasis is dysregulated in hASM cells from subjects with asthma and COPD. [Ca 2+ ] i regulation is central to ASM intrinsic force [ 24 ], as well as agonist-elicited force generation. Moreover, [Ca 2+ ] i regulation is an early signal in cellular proliferation.…”

Interaction between endoplasmic/sarcoplasmic reticulum stress (ER/SR stress), mitochondrial signaling and Ca2+ regulation in airway smooth muscle (ASM)

“…Based on available evidence, it is unlikely that depolarization-dependent Ca 2+ influx is required for the immediate [Ca 2+ ] cyt response to agonist stimulation in ASM (Kannan et al 1997; Prakash et al 1997). However, Ca 2+ influx in ASM does have an important role in establishing basal [Ca 2+ ] cyt levels (Wylam et al 2012) as well as in replenishing depleted SR Ca 2+ stores via store-operated Ca 2+ entry (SOCE) (Ay et al 2004, 2006; White et al 2006; Sieck et al 2008; Sathish et al 2012; Jia et al 2013). …”

Core Role of TRPC6 Channels in Regulating Airway Re-modelling in Chronic Obstructive Pulmonary Disease

“…Ca 2+ signaling is central to agonist-elicited intrinsic contraction force generation in airway smooth muscle 28 . Moreover, it is also a well-known pathway in mediating airway smooth muscle cells proliferation.…”