Nitric Oxide-Dependent Ethanol Stimulation of Ciliary Motility Is Linked to cAMP-Dependent Protein Kinase (PKA) Activation in Bovine Bronchial Epithelium

Sisson, Joseph H.; May, Kathy; Wyatt, Todd A.

doi:10.1097/00000374-199909000-00016

Cited by 15 publications

(27 citation statements)

References 8 publications

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“…Our earlier studies showed that stimulation of PKC blunted A 2A AR-mediated PKA activation2, that PKC activation retards wound repair1920, and that exposure to CSE increases PKC activity2. In this study, we demonstrated that PKC activity is increased in mice expose to CS.…”

Section: Discussionsupporting

confidence: 56%

Cigarette Smoke Impairs A2A Adenosine Receptor Mediated Wound Repair through Up-regulation of Duox-1 Expression

Zhang

Dixon

Traphagen

et al. 2017

Sci Rep

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Cigarette smoke (CS) exposure and intrinsic factors such as the NADPH oxidases produce high levels of reactive oxygen species (ROS), ensuing inflammatory tissue injury. We previously demonstrated that CS-generated ROS, particularly hydrogen peroxide (H2O2), impaired adenosine stimulated wound repair. We hypothesized that CS exposure modulates expression of Dual oxidase 1 (Duox-1), a NADPH oxidases known to generate H2O2. To test this hypothesis, we used human bronchial epithelial cell line Nuli-1 and C57BL/6 mice. Cells were treated with 5% CS extract (CSE) for various periods of time, and mice were exposed to whole body CS for six weeks. Both CSE and CS treatment induced increased expression of Duox-1, and silencing of Doux-1 improved the rate of cell wound repair induced by CSE treatment. Nuli-1 cells pretreated with thapsigargin but not calcium ionophore exhibited increased Duox-1 mRNA expression. CSE treatment stimulated PKCα activation, which was effectively blocked by pretreatment with diphenylene iodonium, a NADPH oxidase inhibitor. Compared to control, lungs from CS-exposed mice showed a significant increase in PKCα activity and Duox-1 expression. Collectively, the data demonstrated that CS exposure upregulates expression of Duox-1 protein. This further leads to H2O2 production and PKCα activation, inhibiting A2AAR-stimulated wound repair.

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Section: Discussionsupporting

confidence: 56%

Cigarette Smoke Impairs A2A Adenosine Receptor Mediated Wound Repair through Up-regulation of Duox-1 Expression

Zhang

Dixon

Traphagen

et al. 2017

Sci Rep

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“…We have previously established that alcohol requires the generation of nitric oxide (NO) to activate the cAMP/PKA pathway (Sisson et al, 1999). We therefore examined the role of NO in the alcohol-mediated inhibition of HDE-stimulated cytokine release.…”

Section: Resultsmentioning

confidence: 99%

“…Our lab has established that alcohol activates the NO pathway, resulting in PKG activation, which is required for the downstream activation of PKA by EtOH (Sisson et al, 1999). Our data show that the NO pathway is also involved with alcohol’s role in diminishing HDE-mediated inflammation.…”

Section: Discussionmentioning

confidence: 99%

“…Chronic alcohol exposure induces cilia desensitization in vitro and in vivo (Wyatt and Sisson, 2001; Elliott et al, 2007). This leads to ineffective mucociliary clearance as alcohol impacts the airway through the nitric oxide (NO) and PKA pathway (Sisson et al, 1999). Alcohol alters airway epithelial innate defense through changes in both NO and the cAMP-dependent protein kinase (PKA) (Wyatt et al, 2003; Wyatt et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

“…Recently, we identified a cyclic AMP-mediated inhibition of the TNFα converting enzyme (TACE) that can block dust-stimulated TNFα release (Wyatt et al, 2014). Because alcohol elevates cAMP in airway epithelium (Sisson et al, 1999), we hypothesized that alcohol exposure blocks dust-mediated TNFα production in airway epithelium through a cAMP-dependent inhibition of TACE activation.…”

Section: Introductionmentioning

confidence: 99%

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Alcohol Decreases Organic Dust‐Stimulated Airway Epithelial TNF‐Alpha Through a Nitric Oxide and Protein Kinase‐Mediated Inhibition of TACE

Gerald

Romberger

DeVasure

et al. 2016

Alcoholism Clin & Exp Res

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Background Farm workers in rural areas consume more alcohol than those who reside in urban areas. Occupational exposures such as agricultural work can pose hazards on the respiratory system. It is established that hog barn dust induces inflammation in the airway, including the release of cytokines such as tumor necrosis factor alpha (TNFα), interleukin-6 (IL-6) and interleukin-8 (IL-8). We have shown that alcohol alters airway epithelial innate defense through changes in both nitric oxide (NO) and cAMP-dependent protein kinase (PKA). Simultaneous exposure to hog barn dust and alcohol decreases inflammatory mediators, TNFα, IL-6 and IL-8, in mice. Previously, mice exposed to both alcohol and hog barn dust showed a depleted amount of lymphocytes compared to mice exposed only to hog barn dust. Weakening of the innate immune response could lead to enhanced susceptibility to disease. In addition, mice that were co-exposed to hog barn dust and alcohol also experienced increased mortality. Methods Because we recently demonstrated that PKA activation inhibits the TNFα sheddase, TNF-α converting enzyme (TACE), we hypothesized that an alcohol-mediated PKA pathway blocks TACE activity and prevents the normative inflammatory response to hog barn dust exposure. To delineate these effects, we used PKA pathway inhibitors (adenylyl cyclase, cAMP and PKA) to modulate the effects of alcohol on dust-stimulated TNFα release in the bronchial epithelial cell line, BEAS-2B. Alcohol pretreatment blocked TACE activity and TNFα release in hog barn dust-treated cells. Results Alcohol continued to block hog barn dust-mediated TNFα release in the presence of the particulate adenylyl cyclase inhibitor, SQ22,536. The soluble adenylyl cyclase (sAC) inhibitor, KH7, however, significantly increased the inflammatory response to hog barn dust. PDE4 inhibitors significantly elevated cAMP and enhanced alcohol-mediated inhibition of dust-stimulated TNFα release. In addition, the nitric oxide synthase inhibitor, L-NMMA, also reversed the alcohol-blocking effect on dust-stimulated TNFα. Conclusions These data suggest that alcohol requires a soluble cyclase-generated cAMP-PKA pathway that is dependent upon the action of NO to inhibit TACE and TNFα release. These findings support our observations that alcohol functions through a dual NO and PKA pathway in bronchial epithelial cells.

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Regulation of ciliary motility: Conserved protein kinases and phosphatases are targeted and anchored in the ciliary axoneme

Wirschell¹,

Yamamoto²,

Alford³

et al. 2011

Archives of Biochemistry and Biophysics

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Recent evidence has revealed that the dynein motors and highly conserved signaling proteins are localized within the ciliary 9 + 2 axoneme. One key mechanism for regulation of motility is phosphorylation. Here, we review diverse evidence, from multiple experimental organisms, that ciliary motility is regulated by phosphorylation / dephosphorylation of the dynein arms through kinases and phosphatases that are anchored immediately adjacent to their axonemal substrates.

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Nitric Oxide-Dependent Ethanol Stimulation of Ciliary Motility Is Linked to cAMP-Dependent Protein Kinase (PKA) Activation in Bovine Bronchial Epithelium

Abstract: We conclude that ethanol stimulates CBF through activating PKA in bovine bronchial epithelial cells and we suggest a cooperative mechanism involving PKA and nitric oxide.

Cited by 15 publications

References 8 publications

Cigarette Smoke Impairs A2A Adenosine Receptor Mediated Wound Repair through Up-regulation of Duox-1 Expression

Cigarette Smoke Impairs A2A Adenosine Receptor Mediated Wound Repair through Up-regulation of Duox-1 Expression

Alcohol Decreases Organic Dust‐Stimulated Airway Epithelial TNF‐Alpha Through a Nitric Oxide and Protein Kinase‐Mediated Inhibition of TACE

Regulation of ciliary motility: Conserved protein kinases and phosphatases are targeted and anchored in the ciliary axoneme

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