Aging causes a slowing in ciliary beat frequency, mediated by PKCε

Bailey, Kristina L.; Bonasera, Stephen J.; Wilderdyke, Marsha R.; Hanisch, Brock W.; Pavlik, Jacqueline A.; DeVasure, Jane M.; Robinson, James E.; Sisson, Joseph H.; Wyatt, Todd A.

doi:10.1152/ajplung.00175.2013

Cited by 37 publications

(38 citation statements)

References 27 publications

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“…Data suggest that this as a dysregulated immune response in aged mice to appropriately respond and resolve repetitive ODE challenges, consistent with our prior observations of diminished ciliary motility/clearance parameters with normal aging (Bailey, et al 2014). Young mice demonstrated an increased CD4:CD8 response that was not found in older mice following repetitive ODE exposure (Figure 4E).…”

Section: Discussionsupporting

confidence: 90%

Age Impacts Pulmonary Inflammation and Systemic Bone Response to Inhaled Organic Dust Exposure

Poole

Romberger

Wyatt

et al. 2015

Journal of Toxicology and Environmental Health, Part A

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Agricultural workers have high rates of airway and skeletal health disease. Studies recently demonstrated that inhaled agricultural organic dust extract (ODE) induced-airway injury is associated with bone deterioration in an animal model. However, the effect of age in governing these responses to organic dusts is unclear, but might be important in future approaches. Young (7–9 weeks) and older (12–14 months) male C57BL/6 mice received intranasal (i.n.) inhalation exposure to ODE from swine confinement facilities once or daily for 3 weeks. Acute ODE-induced neutrophil influx and cytokine and chemokine (TNF-α, IL-6, CXCL1, CXCL2) airway production was reduced in older compared to young mice. Repetitive ODE treatment, however, increased lymphocyte recruitment and alveolar compartment histopathologic inflammatory changes in older mice. Whole lung cell infiltrate analysis revealed that young, but not older mice, repetitively treated with ODE demonstrated an elevated CD4:CD8 lymphocyte response. Acute inhalant ODE exposure resulted in a 4-fold and 1.5-fold rise in blood neutrophils in young and older mice, respectively. Serum IL-6 and CXCL1 levels were elevated in young and older mice i.n. exposed once to ODE, with increased CXCL1 levels in younger compared to older mice. Although older mice displayed reduced bone measurements compared to younger mice, younger rodents demonstrated ODE-induced decrease in bone mineral density, bone volume and bone micro-architecture quality as determined by CT analysis. Collectively, age impacts the airway injury, and systemic inflammatory and bone loss response to inhalant ODE, suggesting an altered and enhanced immunologic response in younger as compared to older counterparts.

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Section: Discussionsupporting

confidence: 90%

Age Impacts Pulmonary Inflammation and Systemic Bone Response to Inhaled Organic Dust Exposure

Poole

Romberger

Wyatt

et al. 2015

Journal of Toxicology and Environmental Health, Part A

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“…Over time, muscles become atrophic, resulting in less strength for effective cough [15]. Also, mucociliary clearance is known to be compromised with age [16], which might in particular contribute to viral and bacterial inflammation and thus acute exacerbations of lung diseases like COPD.…”

Section: The Ageing Lungmentioning

confidence: 99%

Lung ageing and COPD: is there a role for ageing in abnormal tissue repair?

et al. 2017

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Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death worldwide, with increasing prevalence, in particular in the elderly. COPD is characterised by abnormal tissue repair resulting in (small) airways disease and emphysema. There is accumulating evidence that ageing hallmarks are prominent features of COPD. These ageing hallmarks have been described in different subsets of COPD patients, in different lung compartments and also in a variety of cell types, and thus might contribute to different COPD phenotypes. A better understanding of the main differences and similarities between normal lung ageing and the pathology of COPD may improve our understanding of the mechanisms driving COPD pathology, in particular in those patients that develop the most severe form of COPD at a relatively young age, i.e. severe early-onset COPD patients.In this review, after introducing the main concepts of lung ageing and COPD pathology, we focus on the role of (abnormal) ageing in lung remodelling and repair in COPD. We discuss the current evidence for the involvement of ageing hallmarks in these pathological features of COPD. We also highlight potential novel treatment strategies and opportunities for future research based on our current knowledge of abnormal lung ageing in COPD.

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“…The key role of phosphorylation events in AICD led us to hypothesize that phosphatase activity is increased at the cilia organelle level by alcohol (1,8). To test this hypothesis, we directly measured axoneme preparation phosphatase activity after prolonged alcohol exposure.…”

Section: Prolonged Alcohol Increases Phosphatase Activity In Isolatedmentioning

confidence: 99%

Inhibition of protein phosphatase 1 reverses alcohol-induced ciliary dysfunction

Price

Pavlik

Sisson

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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Airway mucociliary clearance is a first-line defense of the lung against inhaled particles and debris. Among individuals with alcohol use disorders, there is an increase in lung diseases. We previously identified that prolonged alcohol exposure impairs mucociliary clearance, known as alcohol-induced ciliary dysfunction (AICD). Cilia-localized enzymes, known as the ciliary metabolon, are key to the pathogenesis of AICD. In AICD, cyclic nucleotide-dependent ciliary kinases, which modulate phosphorylation to regulate cilia beat, are desensitized. We hypothesized that alcohol activates cilia-associated protein phosphatase 1 (PP1) activity, driving phosphorylation changes of cilia motility regulatory proteins. To test this hypothesis we identified the effects of prolonged alcohol exposure on phosphatase activity, cilia beat, and kinase responsiveness and cilia-associated phosphorylation targets when stimulated by β-agonist or cAMP. Prolonged alcohol activated PP1 and blocked cAMP-dependent cilia beat and protein kinase A (PKA) responsiveness and phosphorylation of a 29-kDa substrate of PKA. Importantly, prolonged alcohol-induced phosphatase activation was inhibited by the PP1 specific inhibitor, inhibitor-2 (I-2), restoring cAMP-stimulated cilia beat and PKA responsiveness and phosphorylation of the 29-kDa substrate. The I-2 inhibitory effect persisted in tissue, cell, and isolated cilia-organelle models, highlighting the association of ciliary metabolon-localized enzymes to AICD. Prolonged alcohol exposure drives ciliary metabolon-localized PP1 activation. PP1 activation modifies phosphorylation of a 29-kDa protein related to PKA activity. These data reinforce our previous findings that alcohol is acting at the level of the ciliary metabolon to cause ciliary dysfunction and identifies PP1 as a therapeutic target to prevent or reverse AICD.

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Aging causes a slowing in ciliary beat frequency, mediated by PKCε

Cited by 37 publications

References 27 publications

Age Impacts Pulmonary Inflammation and Systemic Bone Response to Inhaled Organic Dust Exposure

Age Impacts Pulmonary Inflammation and Systemic Bone Response to Inhaled Organic Dust Exposure

Lung ageing and COPD: is there a role for ageing in abnormal tissue repair?

Inhibition of protein phosphatase 1 reverses alcohol-induced ciliary dysfunction

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