Desensitization of PKA‐Stimulated Ciliary Beat Frequency in an Ethanol‐Fed Rat Model of Cigarette Smoke Exposure

Wyatt, Todd A.; Gentry-Nielsen, Martha J.; Pavlik, Jacqueline A.; Sisson, Joseph H.

doi:10.1097/01.alc.0000130805.75641.f4

Cited by 53 publications

(61 citation statements)

References 35 publications

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“…Interestingly, when chronically exposed to ethanol, the effect was quite opposite and ciliary beating was decreased (Wyatt and Sisson, 2001). This chronic desensitization of cilia stimulation by ethanol has also been demonstrated in vivo in rat (Wyatt et al, 2004) and mouse (Elliott et al, 2006) models. Unique to our current study is the observation that maternal transmission of ethanol-mediated desensitization occurs in the full-term lamb as well.…”

Section: Discussionsupporting

confidence: 55%

Maternal alcohol ingestion reduces surfactant protein A expression by preterm fetal lung epithelia

Lazic¹,

Wyatt²,

Matić³

et al. 2007

Alcohol

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In addition to neurodevelopmental effects, alcohol consumption at high levels during pregnancy is associated with immunomodulation and premature birth. Premature birth, in turn, is associated with increased susceptibility to various infectious agents such as Respiratory Syncytial Virus (RSV). The initial line of pulmonary innate defense includes the mucociliary apparatus, which expels microorganisms trapped within the airway secretions. Surfactant proteins A and D (SP-A and SP-D, respectively) are additional components of pulmonary innate immunity and have an important role in pulmonary defense against inhaled pathogens. The purpose of this study was to determine if chronic alcohol consumption during the third trimester of pregnancy alters the function of the mucociliary apparatus and expression of SP-A and SP-D of fetal lung epithelia. Sixteen, date-mated ewes were assigned to two different groups; an ethanol exposed group in which ewes received ethanol through surgically implanted intra-abomasal cannula during the third trimester of pregnancy, and a control group in which ewes received the equivalent amount of water instead of ethanol. Within these two groups, ewes were further randomly assigned to a full-term group in which the lambs were naturally delivered, and a pre-term group in which the lambs were delivered prematurely via an abdominal incision and uterotomy. Ethanol was administered 5 times a week as a 40% solution at 1gr/kg of body weight. The mean maternal serum alcohol concentration (SAC) measured 6 hr post administration was 16.3 +/− 4.36 mg/dL. Tracheas from 6 full-term lambs were collected to assess ciliary beat frequency (CBF). The lung tissue from all (24) lambs was collected for immunohistochemistry (IHC) analysis of SP-A and SP-D protein production and fluorogenic realtime quantitative polymerase chain reaction analysis (qPCR) of SP-A and SP-D mRNA levels. Exposure to ethanol during pregnancy significantly blocked stimulated increase in CBF though ethanol-mediated desensitization of cAMP-dependant protein kinase (PKA). In addition, pre-term born/ethanol-exposed lambs showed significantly decreased SP-A m-RNA expression when compared to the pre-term born/control group (p=0.004); no significant changes were seen with SP-D. The full-term/ethanol exposed lambs had no significant alterations in mRNA levels, but had significantly less detectable SP-A protein when compared to the full-term/control lambs (p=0.02).Corresponding author: Tatjana Lazic, DVM, MS, 2740 Veterinary Medicine, Department of Veterinary Pathology, Iowa State University, Ames, Iowa 50011-1250, 515-294-6688, FAX 515-294-5423, tlazic@iastate.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process error...

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Section: Discussionsupporting

confidence: 55%

Maternal alcohol ingestion reduces surfactant protein A expression by preterm fetal lung epithelia

Lazic¹,

Wyatt²,

Matić³

et al. 2007

Alcohol

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“…Subsequent studies in bovine tracheal ciliated cells established that alcohol stimulation of CBF was dependent on nitric oxide production in airway epithelium (Sisson, 1995) and required the dual activation of both cyclic AMP-and cyclic GMP-dependent protein kinases, PKA and PKG, in ciliated cells (Sisson et al, 1999;Wyatt et al, 2003). This transient alcohol stimulation effect on cilia was recapitulated in vivo in alcohol-fed rats (Wyatt et al, 2004). In this model, 1 week of feeding 36% alcohol increased baseline CBF 40% over control animals and was comparable to stimulation with an exogenous beta agonist.…”

Section: Basic Science Studies Of Alcohol and Mucociliary Clearancementioning

confidence: 95%

Alcohol and airways function in health and disease

Sisson

2007

Alcohol

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The volatility of alcohol promotes the movement of alcohol from the bronchial circulation across the airway epithelium and into the conducting airways of the lung. The exposure of the airways through this route likely accounts for many of the biologic effects of alcohol on lung airway functions. The impact of alcohol on lung airway functions is dependent on the concentration, duration and route of exposure. Brief exposure to mild concentrations of alcohol may enhance mucociliary clearance, stimulates bronchodilation and probably attenuates the airway inflammation and injury observed in asthma and COPD. Prolonged and heavy exposure to alcohol impairs mucociliary clearance, may complicate asthma management and likely worsens outcomes including lung function and mortality in COPD patients. Non-alcohol congeners and alcohol metabolites act as triggers for airway disease exacerbations especially in atopic asthmatics and in Asian populations who have a reduced capacity to metabolize alcohol. Research focused on the mechanisms of alcohol-mediated changes in airway functions has identified specific mechanisms that mediate alcohol effects within the lung airways. These include prominent roles for the second messengers calcium and nitric oxide, regulatory kinases including PKG and PKA, alcohol and acetaldehyde-metabolizing enzymes such as aldehyde dehydrogenase type 2 (ALDH2). The role alcohol may play in the pathobiology of airway mucus, bronchial blood flow, airway smooth muscle regulation and the interaction with other airway exposure agents, such as cigarette smoke, represent opportunities for future investigation.

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“…(38) Ethanol, a biological agent shown to decrease beta agoniststimulated CBF, is linked to cAMP-dependent protein kinase (PKA) desensitization in an in vivo model. (21) To maximally stimulate CBF in axonemes, both cAMP and cGMP are required to activate their respective protein kinase pathways (PKA and PKG). (19) Therefore, the NPs > 200 nm and CS might initiate elevated CBF in the axoneme by activating PKA or PKG, even though signaling pathways in the intact cell may involve PKC-activated CBF decreases in response to CS.…”

Section: Discussionmentioning

confidence: 99%

“…Because in vitro studies have been inconclusive on whether CSE exposure results in CBF stimulation or inhibition (7)(8)(9)11,21) we assayed CBF in a cell-free preparation of ciliary axonemes exposed to CSE. Given the high incidence of pulmonary disease in tobacco users, we hypothesized that CSE would alter CBF in a cell-free axoneme model.…”

Section: Introductionmentioning

confidence: 99%

Particulate Matter in Cigarette Smoke Increases Ciliary Axoneme Beating Through Mechanical Stimulation

Navarrette¹,

Sisson²,

Nance

et al. 2012

Journal of Aerosol Medicine and Pulmonary Drug Delivery

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Background: The lung's ability to trap and clear foreign particles via the mucociliary elevator is an important mechanism for protecting the lung against respirable irritants and microorganisms. Although cigarette smoke (CS) exposure and particulate inhalation are known to alter mucociliary clearance, little is known about how CS and nanoparticles (NPs) modify cilia beating at the cytoskeletal infrastructure, or axonemal, level. Methods: We used a cell-free model to introduce cigarette smoke extract (CSE) and NPs with variant size and surface chemistry to isolated axonemes and measured changes in ciliary motility. We hypothesized that CSE would alter cilia beating and that alterations in ciliary beat frequency (CBF) due to particulate matter would be size-and surface chemistry-dependent. Demembranated axonemes were isolated from ciliated bovine tracheas and exposed to adenosine triphosphate (ATP) to initiate motility. CBF was measured in response to 5% CSE, CSE filtrate, and carboxyl-modified (COOH), sulphate (SO 4 )-modified (sulfonated), or PEG-coated polystyrene (PS) latex NPs ranging in size from 40 nm to 500 nm. Results: CSE concentrations as low as 5% resulted in rapid, significant stimulation of CBF ( p < 0.05 vs. baseline control). Filtering CSE through a 0.2-lm filter attenuated this effect. Introduction of sulphate-modified PS beads *300 nm in diameter resulted in a similar increase in CBF above baseline ATP levels. Uncharged, PEG-coated beads had no effect on CBF regardless of size. Similarly, COOH-coated particles less than 200 nm in diameter did not alter ciliary motility. However, COOH-coated PS particles larger than 300 nm increased CBF significantly and increased the number of motile points. Conclusions: These data show that NPs, including those found in CSE, mechanically stimulate axonemes in a size-and surface chemistry-dependent manner. Alterations in ciliary motility due to physicochemical properties of NPs may be important for inhalational lung injury and efficient drug delivery of respirable particles.

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Desensitization of PKA‐Stimulated Ciliary Beat Frequency in an Ethanol‐Fed Rat Model of Cigarette Smoke Exposure

Cited by 53 publications

References 35 publications

Maternal alcohol ingestion reduces surfactant protein A expression by preterm fetal lung epithelia

Maternal alcohol ingestion reduces surfactant protein A expression by preterm fetal lung epithelia

Alcohol and airways function in health and disease

Particulate Matter in Cigarette Smoke Increases Ciliary Axoneme Beating Through Mechanical Stimulation

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