Aging Enhances Susceptibility to Cigarette Smoke–Induced Inflammation through Bronchiolar Chemokines

Moriyama, Chinatsu; Betsuyaku, Tomoko; Ito, Yoko; Hamamura, Ichiro; Hata, J. Steven; Takahashi, Hiroshi; Nasuhara, Yasuyuki; Nishimura, Masaharu

doi:10.1165/rcmb.2009-0025oc

Cited by 30 publications

(25 citation statements)

References 38 publications

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“…This progression parallels persisting inflammatory responses (83), suggesting that additional mechanisms must account for the consolidation of the disease in genetically susceptible hosts, often after decades of active smoking ( Figure 1). This change in the nature of inflammation in the course of disease is highlighted by the temporary nature of NF-κB activation in rodent lungs exposed to cigarette smoke (84). Two paradigms have emerged that might explain some of these observations: autoimmunity (52) and lung aging (85).…”

Section: Consolidationmentioning

confidence: 99%

Pathogenesis of chronic obstructive pulmonary disease

Tuder¹,

Petrache²

2012

J. Clin. Invest.

410

322

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The current epidemic of chronic obstructive pulmonary disease (COPD) has produced a worldwide health care burden, approaching that imposed by transmittable infectious diseases. COPD is a multidimensional disease, with varied intermediate and clinical phenotypes. This Review discusses the pathogenesis of COPD, with particular focus on emphysema, based on the concept that pulmonary injury involves stages of initiation (by exposure to cigarette smoke, pollutants, and infectious agents), progression, and consolidation. Tissue damage entails complex interactions among oxidative stress, inflammation, extracellular matrix proteolysis, and apoptotic and autophagic cell death. Lung damage by cigarette smoke ultimately leads to self-propagating processes, resulting in macromolecular and structural alterations -features similar to those seen in aging.

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Section: Consolidationmentioning

confidence: 99%

Pathogenesis of chronic obstructive pulmonary disease

Tuder¹,

Petrache²

2012

J. Clin. Invest.

410

322

View full text Add to dashboard Cite

show abstract

“…It has been reported that older mice develop a greater inflammatory response, either spontaneously or after smoke exposure, compared to young mice ([8]–[10], and see Discussion), and conversely, a decreased antioxidant response [10], [11]. However, whether older animals actually develop worse COPD compared to younger has not been examined.…”

Section: Introductionmentioning

confidence: 95%

Aging does not Enhance Experimental Cigarette Smoke-Induced COPD in the Mouse

et al. 2013

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It has been proposed that the development of COPD is driven by premature aging/premature senescence of lung parenchyma cells. There are data suggesting that old mice develop a greater inflammatory and lower anti-oxidant response after cigarette smoke compared to young mice, but whether these differences actually translate into greater levels of disease is unknown. We exposed C57Bl/6 female mice to daily cigarette smoke for 6 months starting at age 3 months (Ayoung@) or age 12 months (Aold@), with air-exposed controls. There were no differences in measures of airspace size between the two control groups and cigarette smoke induced exactly the same amount of emphysema in young and old. The severity of smoke-induced small airway remodeling using various measures was identical in both groups. Smoke increased numbers of tissue macrophages and neutrophils and levels of 8-hydroxyguanosine, a marker of oxidant damage, but there were no differences between young and old. Gene expression studies using laser capture microdissected airways and parenchyma overall showed a trend to lower levels in older animals and a somewhat lesser response to cigarette smoke in both airways and parenchyma but the differences were usually not marked. Telomere length was greatest in young control mice and was decreased by both smoking and age. The senescence marker p21Waf1 was equally upregulated by smoke in young and old, but p16INK4a, another senescence marker, was not upregulated at all. We conclude, in this model, animal age does not affect the development of emphysema and small airway remodeling.

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“…COPD is characterized by destruction of alveolar wall, inflammatory response, and premature lung aging or cellular senescence (Nyunoya et al, 2006; Moriyama et al, 2010; Yao et al, 2012; Ahmad et al, 2015). Pro-inflammatory mediators such as IL-8 (mouse KC) and MIP-2, act as CXCR2 ligands, which are critical for recruitment of peripheral neutrophils.…”

Section: Introductionmentioning

confidence: 99%

Genetic Ablation of CXCR2 Protects against Cigarette Smoke-Induced Lung Inflammation and Injury

et al. 2016

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Antagonism of CXCR2 receptors, predominately located on neutrophils and critical for their immunomodulatory activity, is an attractive pharmacological therapeutic approach aimed at reducing the potentially damaging effects of heightened neutrophil influx into the lung. The role CXCR2 in lung inflammation in response to cigarette smoke (CS) inhalation using the mutant mouse approach is not known. We hypothesized that genetic ablation of CXCR2 would protect mice against CS-induced inflammation and DNA damage response. We used CXCR2−/− deficient/mutant (knock-out, KO) mice, and assessed the changes in critical lung inflammatory NF-κB-driven chemokines released from the parenchyma of CS-exposed mice. The extent of tissue damage was assessed by the number of DNA damaging γH2AX positive cells. CXCR2 KO mice exhibited protection from heightened levels of neutrophils measured in BALF taken from mice exposed to CS. IL-8 (KC mouse) levels in the BALF from CS-exposed CXCR2 KO were elevated compared to WT. IL-6 levels in BALF were refractory to increase by CS in CXCR2 KO mice. There were no significant changes to MIP-2, MCP-1, or IL-1β. Total levels of NF-κB were maintained at lower levels in CS-exposed CXCR2 KO mice compared to WT mice exposed to CS. Finally, CXCR2 KO mice were protected from lung cells positive for DNA damage response and senescence marker γH2AX. CXCR2 KO mice are protected from heightened inflammatory response mediated by increased neutrophil response as a result of acute 3 day CS exposure. This is also associated with changes in pro-inflammatory chemokines and reduced incursion of γH2AX indicating CXCR2 deficient mice are protected from lung injury. Thus, CXCR2 may be a pharmacological target in setting of inflammation and DNA damage in the pathogenesis of COPD.

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Aging Enhances Susceptibility to Cigarette Smoke–Induced Inflammation through Bronchiolar Chemokines

Cited by 30 publications

References 38 publications

Pathogenesis of chronic obstructive pulmonary disease

Pathogenesis of chronic obstructive pulmonary disease

Aging does not Enhance Experimental Cigarette Smoke-Induced COPD in the Mouse

Genetic Ablation of CXCR2 Protects against Cigarette Smoke-Induced Lung Inflammation and Injury

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