Characterization of cigarette smoke-induced inflammatory and mucus hypersecretory changes in rat lung and the role of CXCR2 ligands in mediating this effect

Stevenson, Christopher S.; Coote, Kevin; Webster, Ruth; Johnston, Helinor Jane; Atherton, Hazel; Nicholls, Andrew; Giddings, June; Sugar, Rosemary; Jackson, A D; Press, Neil J.; Brown, Zarin; Butler, K.D.; Danahay, Henry

doi:10.1152/ajplung.00317.2004

Cited by 84 publications

(73 citation statements)

References 27 publications

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“…In the CS-only and O 2 1CS mice, we found increased numbers of inflammatory cells in the BALF and increased expression of CXCR2/IL8Ra lung mRNA, suggesting a correlation between chronic CS exposure and increased lung inflammation. Induction of CXCR2/IL8Ra has previously been demonstrated in animal models of CSinduced COPD, Streptococcus pneumoniae, and rhinovirusinduced airway inflammation (30)(31)(32)(33). We did not find an association between early postnatal hyperoxia exposure and increased inflammation in the adult lung.…”

Section: Discussioncontrasting

confidence: 55%

Neonatal Hyperoxia Contributes Additively to Cigarette Smoke–Induced Chronic Obstructive Pulmonary Disease Changes in Adult Mice

McGrath‐Morrow¹,

Lauer²,

Collaco³

et al. 2011

Am J Respir Cell Mol Biol

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The extent by which early postnatal lung injury contributes to the development of chronic obstructive pulmonary disease (COPD) in the adult is unclear. We hypothesized that exposure to hyperoxia during early postnatal life can augment lung changes caused by adult chronic cigarette smoke (CS) exposure. C57BL/6J mice (1 d old) were exposed to hyperoxia (O 2 ) for 5 days. At 1 month of age, half of the O 2 -exposed mice and half of the control mice were placed in a CS chamber for 6 months. After exposure to CS, mice underwent quasistatic pressure-volume curve and mean chord length measurements; quantification of pro-Sp-c expression; and measurement of lung IL-8/ KC, CXCR2/IL8Ra, TNF-a, and IL-6 mRNA by real-time PCR. Adult mice exposed to O 2 1CS had significantly larger chord length measurements (P , 0.02) and lung volumes at 35 cm H 2 O (P , 0.05) compared with all other groups. They also had significantly less proSp-c protein and surfactant protein C mRNA expression (P , 0.003). Mice exposed to O 2 1CS and CS-only mice had significantly higher lung resistance and longer mean time constants (P , 0.01), significantly more inflammatory cells in the bronchoalveolar lavage fluid (P , 0.03), and significantly higher levels of lung CXCR2/IL8Ra mRNA compared with mice not exposed to smoke (P , 0.02). We conclude that exposure to early postnatal hyperoxia contributed additively to CS-induced COPD changes in adult mice. These results may be relevant to a growing population of preterm children who sustained lung injury in the newborn period and may be exposed to CS in later life.

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Section: Discussioncontrasting

confidence: 55%

Neonatal Hyperoxia Contributes Additively to Cigarette Smoke–Induced Chronic Obstructive Pulmonary Disease Changes in Adult Mice

McGrath‐Morrow¹,

Lauer²,

Collaco³

et al. 2011

Am J Respir Cell Mol Biol

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“…Animals were sacrificed 24 hours with bronchiolar lavage and differential cell counts performed as previously described (27).…”

Section: Cellmentioning

confidence: 99%

“…mice have been described previously (25;26). Mice were exposed to either cigarette smoke (5x1R3F cigarettes/day) or room-air on 3 consecutive days as previously described (27) and dosed with either budesonide (1mg/kg) or vehicle (saline with 2% NMP) by intranasal (i.n. )…”

Section: Introductionmentioning

confidence: 99%

Inhibition of PI3Kδ Restores Glucocorticoid Function in Smoking-induced Airway Inflammation in Mice

Marwick

Caramori²,

Stevenson³

et al. 2009

Am J Respir Crit Care Med

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221

180

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Scientific Knowledge on the Subject: Glucocorticoid unresponsiveness in severe asthma COPD may involve an oxidant mediated impairment of glucocorticoid receptor alpha (GRα) function through reduction of histone deacetylase activity and co-repressor expression.What This Study Adds to the Field: Histone deacetylase 2 activity is reduced in smoke exposed mice lungs correlating with reduced glucocorticoid function which is restored by PI3Kδ but not γ inhibition. GRα expression also is reduced in smoke exposed mouse and in COPD patient lungs. Abstract Rational:There is an increasing prevalence of reduced responsiveness to glucocorticoid therapy in severe asthma and chronic obstructive pulmonary disease, however the molecular mechanism of this remains unknown. Recent studies have shown that histone deacetylase activity, which is critical to glucocorticoid function, is altered by oxidant stress and may be involved in the development of glucocorticoid insensitivity.Objectives: To determine the role of phosphoinositol-3-kinase (PI3K) in the development of cigarette smoke induced glucocorticoid insensitivity. Methods:Wild type, PI3Kγ knock-out and PI3Kδ kinase dead knock-in transgenic mice were used in a model of cigarette smoke induced glucocorticoid insensitivity. Peripheral lung tissue was obtained 6 healthy non-smokers, 9 smokers with normal lung function and 8 patients with chronic obstructive pulmonary disease. Measurements and Main Results:Glucocorticoid receptor expression was significantly reduced in both the lungs of chronic obstructive pulmonary disease patients and in cigarette smoke-exposed mice. Furthermore, cigarette smoke exposure in mice increased tyrosine nitration of histone deacetylase 2 in the lung correlating with both reduced histone deacetylase 2 activity and reduced glucocorticoid function. Oxidative stress activated Akt and induced glucocorticoid insensitivity in vitro, which was restored by inhibition of PI3K. In vivo, histone deacetylase 2 activity and the anti-inflammatory effects of glucocorticoids were restored in PI3Kδ kinase dead knock-in but not PI3Kγ knock-out smoke exposed mice compared to wild types, correlating with reduced histone deacetylase 2 tyrosine nitration.Conclusion: Together these data shows that therapeutic inhibition of PI3Kδ may restore glucocorticoid function in oxidative stress induced glucocorticoid insensitivity. Abstract Word count: 247

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“…CXCL8 (previously known as IL-8) is a potent PMN chemoattractant; unsurprisingly, CXCL8 concentrations in sputum and BAL fluid correlate with increased PMN accumulation (75). In rodent models of cigarette smoke exposure, a small molecule inhibitor of CXCR2 reduced PMN influx to the lungs (76,77). Several CXCR2 inhibitors are now in clinical development for COPD (78).…”

Section: Lung Inflammation In Copd: Ongoing Recruitment Versus In Sitmentioning

confidence: 99%

The Immunopathogenesis of Chronic Obstructive Pulmonary Disease: Insights from Recent Research

Curtis¹,

Freeman²,

Hogg³

2007

Proceedings of the American Thoracic Society

169

145

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Chronic obstructive pulmonary disease (COPD) progression is characterized by accumulation of inflammatory mucous exudates in the lumens of small airways, and thickening of their walls, which become infiltrated by innate and adaptive inflammatory immune cells. Infiltration of the airways by polymorphonuclear and mononuclear phagocytes and CD4 T cells increases with COPD stage, but the cumulative volume of the infiltrate does not change. By contrast, B cells and CD8 T cells increase in both the extent of their distribution and in accumulated volume, with organization into lymphoid follicles. This chronic lung inflammation is also associated with a tissue repair and remodeling process that determines the ultimate pathologic phenotype of COPD. Why these pathologic abnormalities progress in susceptible individuals, even after removal of the original noxious stimuli, remains mysterious. However, important clues are emerging from analysis of pathologic samples from patients with COPD and from recent discoveries in basic immunology. We consider the following relevant information: normal limitations on the innate immune system's ability to generate adaptive pulmonary immune responses and how they might be overcome by tobacco smoke exposure; the possible contribution of autoimmunity to COPD pathogenesis; and the potential roles of ongoing lymphocyte recruitment versus in situ proliferation, of persistently activated resident lung T cells, and of the newly described T helper 17 (Th17) phenotype. We propose that the severity and course of acute exacerbations of COPD reflects the success of the adaptive immune response in appropriately modulating the innate response to pathogen-related molecular patterns ("the Goldilocks hypothesis").

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Characterization of cigarette smoke-induced inflammatory and mucus hypersecretory changes in rat lung and the role of CXCR2 ligands in mediating this effect

Abstract: . Characterization of cigarette smoke-induced inflammatory and mucus hypersecretory changes in rat lung and the role of CXCR2 ligands in mediating this effect.

Cited by 84 publications

References 27 publications

Neonatal Hyperoxia Contributes Additively to Cigarette Smoke–Induced Chronic Obstructive Pulmonary Disease Changes in Adult Mice

Neonatal Hyperoxia Contributes Additively to Cigarette Smoke–Induced Chronic Obstructive Pulmonary Disease Changes in Adult Mice

Inhibition of PI3Kδ Restores Glucocorticoid Function in Smoking-induced Airway Inflammation in Mice

The Immunopathogenesis of Chronic Obstructive Pulmonary Disease: Insights from Recent Research

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