Gα<sub>12</sub> facilitates shortening in human airway smooth muscle by modulating phosphoinositide 3‐kinase‐mediated activation in a RhoA‐dependent manner

Yoo, Eung Jae; Cao, Gaoyuan; Koziol‐White, Cynthia; Ojiaku, Christie A.; Sunder, Krishna; Jude, Joseph; Michael, James V.; Lam, Hong; Pushkarsky, Ivan; Damoiseaux, Robert; Carlo, Dino Di; Ahn, Kwangmi; An, Steven S.; Penn, Raymond B.; Panettieri, Reynold A.

doi:10.1111/bph.14040

Cited by 30 publications

(23 citation statements)

References 51 publications

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“…Studies show that thioredoxin-dependent antioxidant mechanisms are upregulated in airway epithelial cells in response to exposure to pathogens and toxicants to confer protection [42, 43], suggesting similar mechanisms may be at play in hPCLS exposed to TDI. In order to test this hypothesis, future studies should directly measure cell shortening in HASM cells co-cultured with ALI-differentiated epithelial cells and treated with TDI [35, 44].…”

Section: Discussionmentioning

confidence: 99%

Salicylic acid amplifies Carbachol-induced bronchoconstriction in human precision-cut lung slices

et al. 2019

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Background Asthma exacerbations evoke emergency room visits, progressive loss of lung function and increased mortality. Environmental and industrial toxicants exacerbate asthma, although the underlying mechanisms are unknown. We assessed whether 3 distinct toxicants, salicylic acid (SA), toluene diisocyanate (TDI), and 1-chloro-2,4-dinitrobenzene (DNCB) induced airway hyperresponsiveness (AHR) through modulating excitation-contraction coupling in human airway smooth muscle (HASM) cells. The toxicants include a non-sensitizing irritant (SA), respiratory sensitizer (TDI) and dermal sensitizer (DNCB), respectively. We hypothesized that these toxicants induce AHR by modulating excitation-contraction (EC) coupling in airway smooth muscle (ASM) cells. Methods Carbachol-induced bronchoconstriction was measured in precision-cut human lung slices (hPCLS) following exposure to SA, TDI, DNCB or vehicle. Culture supernatants of hPCLS were screened for mediator release. In HASM cells treated with the toxicants, surrogate readouts of EC coupling were measured by phosphorylated myosin light chain (pMLC) and agonist-induced Ca 2+ mobilization ([Ca 2+ ] i ). In addition, Nrf-2-dependent antioxidant response was determined by NAD(P) H quinone oxidoreductase 1 (NQO1) expression in HASM cells. Results In hPCLS, SA, but not TDI or DNCB, potentiated carbachol-induced bronchoconstriction. The toxicants had little effect on release of inflammatory mediators, including IL-6, IL-8 and eotaxin from hPCLS. In HASM cells, TDI amplified carbachol-induced MLC phosphorylation. The toxicants also had little effect on agonist-induced [Ca 2+ ] i. Conclusion SA, a non-sensitizing irritant, amplifies agonist-induced bronchoconstriction in hPCLS via mechanisms independent of inflammation and Ca 2+ homeostasis in HASM cells. The sensitizers TDI and DNCB, had little effect on bronchoconstriction or inflammatory mediator release in hPCLS. Implications Our findings suggest that non-sensitizing irritant salicylic acid may evoke AHR and exacerbate symptoms in susceptible individuals or in those with underlying lung disease. Electronic supplementary material The online version of this article (10.1186/s12931-019-1034-x) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Salicylic acid amplifies Carbachol-induced bronchoconstriction in human precision-cut lung slices

et al. 2019

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“…IL-13 has been shown to augment canonical calcium mobilization pathways 21 , and enhance calcium sensitization pathways 34 . Additionally, inhibition of RhoA induced relaxation of methacholine-constricted human small airways 35 . TGFβ1-induced phosphorylation of MLC was found to be ROCK-dependent in human ASM 23 .…”

Section: Modulation Of Asm Pro-contractile Pathways In Asthmamentioning

confidence: 97%

Modulation of Bronchomotor Tone Pathways in Airway Smooth Muscle Function and Bronchomotor Tone in Asthma

Koziol‐White

Panettieri

2019

Clinics in Chest Medicine

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“…In cultured A7r5 rat embryonic aorta smooth muscle cells, ROCK-mediated phosphorylation of MYPT1 at Thr 695 is similar to that of phosphorylation of human MYPT1 at Thr 696 , and phosphorylation of rat MYPT1 at Thr 850 is similar to that of phosphorylation of human MYPT1 at Thr 853 ( Murányi et al, 2005 ). In a guinea pig model of asthma and in airway smooth muscle from asthma patients, increased phosphorylation of MYPT1 occurs at Thr 696 ( Álvarez-Santos et al, 2016 ; Yoo et al, 2017 ). In addition, phosphorylation of MYPT1 at Thr 696 by ROCK in bovine airway smooth muscle inhibits MLCP activity, although Thr 853 phosphorylation does not alter its phosphatase activity ( Gao et al, 2017 ).…”

Section: Rho-associated Kinase (Rock) Is a Key Regulator Of Airway Smmentioning

confidence: 99%

Regulation of Myosin Light-Chain Phosphatase Activity to Generate Airway Smooth Muscle Hypercontractility

et al. 2020

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Smooth muscle is a central structure involved in the regulation of airway tone. In addition, it plays an important role in the development of some pathologies generated by alterations in contraction, such as hypercontractility and the airway hyperresponsiveness observed in asthma. The molecular processes associated with smooth muscle contraction are centered around myosin light chain (MLC) phosphorylation, which is controlled by a balance in the activity of myosin light-chain kinase (MLCK) and myosin light-chain phosphatase (MLCP). MLCK activation depends on increasing concentrations of intracellular Ca 2+ , while MLCP activation is independent of Ca 2+. MLCP contains a phosphatase subunit (PP1c) that is regulated through myosin phosphatase target subunit 1 (MYPT1) and other subunits, such as glycogenassociated regulatory subunit and myosin-binding subunit 85 kDa. Interestingly, MLCP inhibition may contribute to exacerbation of smooth muscle contraction by increasing MLC phosphorylation to induce hypercontractility. Many pathways inhibiting MLCP activity in airway smooth muscle have been proposed and are focused on inhibition of PP1c, inhibitory phosphorylation of MYPT1 and dissociation of the PP1c-MYPT1 complex.

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Gα₁₂ facilitates shortening in human airway smooth muscle by modulating phosphoinositide 3‐kinase‐mediated activation in a RhoA‐dependent manner

Cited by 30 publications

References 51 publications

Salicylic acid amplifies Carbachol-induced bronchoconstriction in human precision-cut lung slices

Salicylic acid amplifies Carbachol-induced bronchoconstriction in human precision-cut lung slices

Modulation of Bronchomotor Tone Pathways in Airway Smooth Muscle Function and Bronchomotor Tone in Asthma

Regulation of Myosin Light-Chain Phosphatase Activity to Generate Airway Smooth Muscle Hypercontractility

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Gα12 facilitates shortening in human airway smooth muscle by modulating phosphoinositide 3‐kinase‐mediated activation in a RhoA‐dependent manner

Cited by 30 publications

References 51 publications

Salicylic acid amplifies Carbachol-induced bronchoconstriction in human precision-cut lung slices

Salicylic acid amplifies Carbachol-induced bronchoconstriction in human precision-cut lung slices

Modulation of Bronchomotor Tone Pathways in Airway Smooth Muscle Function and Bronchomotor Tone in Asthma

Regulation of Myosin Light-Chain Phosphatase Activity to Generate Airway Smooth Muscle Hypercontractility

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Gα₁₂ facilitates shortening in human airway smooth muscle by modulating phosphoinositide 3‐kinase‐mediated activation in a RhoA‐dependent manner