Noninvasive and Invasive Pulmonary Function in Mouse Models of Obstructive and Restrictive Respiratory Diseases

Vanoirbeek, Jeroen; Rinaldi, Manuela; Vooght, Vanessa De; Haenen, Steven; Bobic, Sonja; Gayan‐Ramirez, Ghislaine; Hoet, Peter; Verbeken, Erik; Decramer, Marc; Nemery, Benoît; Janssens, Wim

doi:10.1165/rcmb.2008-0487oc

Cited by 288 publications

(266 citation statements)

References 43 publications

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“…These changes were accompanied by alveolar destruction and impairments in lung function. Interestingly, our experiments in lung function reveal that contrary to previously reported data (42), increased airway resistance and elastance were observed. These observations included both dynamic and PV-loop data under quasistatic conditions.…”

Section: Discussioncontrasting

confidence: 99%

Adenosine A2B Receptor and Hyaluronan Modulate Pulmonary Hypertension Associated with Chronic Obstructive Pulmonary Disease

Karmouty‐Quintana¹,

Weng

Garcia-Morales

et al. 2013

Am J Respir Cell Mol Biol

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Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death worldwide. The development of pulmonary hypertension (PH) in patients with COPD is strongly associated with increased mortality. Chronic inflammation and changes to the lung extracellular matrix (ECM) have been implicated in the pathogenesis of COPD, yet the mechanisms that lead to PH secondary to COPD remain unknown. Our experiments using human lung tissue show increased expression levels of the adenosine A 2B receptor (ADORA2B) and a heightened deposition of hyaluronan (HA; a component of the ECM) in remodeled vessels of patients with PH associated with COPD. We also demonstrate that the expression of HA synthase 2 correlates with mean pulmonary arterial pressures in patients with COPD, with and without a secondary diagnosis of PH. Using an animal model of airspace enlargement and PH, we show that the blockade of ADORA2B is able to attenuate the development of a PH phenotype that correlates with reduced levels of HA deposition in the vessels and the down-regulation of genes involved in the synthesis of HA.Keywords: adenosine; extracellular matrix; hyaluronic acid; remodeling; vascular Chronic obstructive pulmonary disease (COPD) is currently the fourth leading cause of death worldwide, and the World Health Organization predicts that it will become the third leading cause of death by 2030 (1). COPD is a heterogeneous disease characterized by airflow obstruction that is not fully reversible. Pathophysiological hallmarks of the disease include remodeling of the smallairway compartment, the loss of elastic recoil by emphysematous destruction of the parenchyma, inflammatory cell infiltration (2), and increased extracellular matrix (ECM) turnover (3). COPD is associated with a wide range of comorbidities, including ischemic heart disease, diabetes, skeletal muscle wasting, osteoporosis, and lung cancer (4). The development of pulmonary hypertension (PH) is a common and fatal complication in patients with COPD (5-7), and is strongly associated with decreased life expectancy (8).PH is a disorder of the pulmonary vasculature diagnosed by cardiac catheterization. PH is characterized by a mean pulmonary arterial pressure greater than or equal to 25 mm Hg that leads to right ventricular (RV) hypertrophy, followed by right-sided heart failure and death (9). Currently, treatment options are very limited for patients suffering from PH secondary to COPD (10, 11). Thus, to understand the mechanisms that lead to remodeling of the vasculature in COPD is important, with the hope of developing new treatment options for this fatal disorder.The pathogenesis of PH in COPD is a complex phenomenon characterized by extensive remodeling of the vasculature that results from an increased proliferation of pulmonary artery endothelial and smooth muscle cells, the muscularization of previously nonmuscular arteries, increased vascular tone, and the formation of complex vascular lesions (12). Factors involved in the development of PH in patients with COPD include ...

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Section: Discussioncontrasting

confidence: 99%

Adenosine A2B Receptor and Hyaluronan Modulate Pulmonary Hypertension Associated with Chronic Obstructive Pulmonary Disease

Karmouty‐Quintana¹,

Weng

Garcia-Morales

et al. 2013

Am J Respir Cell Mol Biol

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“…In agreement with the previous studies (40,41), chronic CS exposure did not alter R L , which was significantly decreased in elastaseexposed mice, suggesting that the reduction of R L occurs only in the setting of more severe emphysema. This was further corroborated by the findings in Sirt1-deficient mice, which exhibited lower R L and enhanced airspace enlargement than did WT littermates in response to both chronic CS and elastase exposures.…”

Section: Discussionsupporting

confidence: 93%

SIRT1 protects against emphysema via FOXO3-mediated reduction of premature senescence in mice

Yao

Chung²,

Hwang³

et al. 2012

J. Clin. Invest.

315

351

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Chronic obstructive pulmonary disease/emphysema (COPD/emphysema) is characterized by chronic inflammation and premature lung aging. Anti-aging sirtuin 1 (SIRT1), a NAD + -dependent protein/histone deacetylase, is reduced in lungs of patients with COPD. However, the molecular signals underlying the premature aging in lungs, and whether SIRT1 protects against cellular senescence and various pathophysiological alterations in emphysema, remain unknown. Here, we showed increased cellular senescence in lungs of COPD patients. SIRT1 activation by both genetic overexpression and a selective pharmacological activator, SRT1720, attenuated stress-induced premature cellular senescence and protected against emphysema induced by cigarette smoke and elastase in mice. Ablation of Sirt1 in airway epithelium, but not in myeloid cells, aggravated airspace enlargement, impaired lung function, and reduced exercise tolerance. These effects were due to the ability of SIRT1 to deacetylate the FOXO3 transcription factor, since Foxo3 deficiency diminished the protective effect of SRT1720 on cellular senescence and emphysematous changes. Inhibition of lung inflammation by an NF-κB/IKK2 inhibitor did not have any beneficial effect on emphysema. Thus, SIRT1 protects against emphysema through FOXO3-mediated reduction of cellular senescence, independently of inflammation. Activation of SIRT1 may be an attractive therapeutic strategy in COPD/emphysema.

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“…Similarly, we observed alterations in central airway pulmonary mechanics in Sftpd 2/2 mice relative to Sftpd 1/1 mice, as measured by increases in R, Rn, and Cst (39). In addition, at all PEEPs measured, R L was greater at high frequencies, suggesting that persistent pulmonary inflammation in Sftpd 2/2 mice leads to alterations in central airway mechanics.…”

Section: Discussionsupporting

confidence: 69%

Prolonged Injury and Altered Lung Function after Ozone Inhalation in Mice with Chronic Lung Inflammation

Groves

Gow

Massa

et al. 2012

Am J Respir Cell Mol Biol

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Surfactant protein-D (Sftpd) is a pulmonary collectin important in down-regulating macrophage inflammatory responses. In these experiments, we analyzed the effects of chronic macrophage inflammation attributable to loss of Sftpd on the persistence of ozoneinduced injury, macrophage activation, and altered functioning in the lung. Wild-type (Sftpd 1/1 ) and Sftpd 2/2 mice (aged 8 wk) were exposed to air or ozone (0.8 parts per million, 3 h). Bronchoalveolar lavage (BAL) fluid and tissue were collected 72 hours later. In Sftpd 2/2 mice, but not Sftpd 1/1 mice, increased BAL protein and nitrogen oxides were observed after ozone inhalation, indicating prolonged lung injury and oxidative stress. Increased numbers of macrophages were also present in BAL fluid and in histologic sections from Sftpd 2/2 mice. These cells were enlarged and foamy, suggesting that they were activated. This conclusion was supported by findings of increased BAL chemotactic activity, and increased expression of inducible nitric oxide synthase in lung macrophages. In both Sftpd 1/1 and Sftpd 2/2 mice, inhalation of ozone was associated with functional alterations in the lung. Although these alterations were limited to central airway mechanics in Sftpd 1/1 mice, both central airway and parenchymal mechanics were modified by ozone exposure in Sftpd 2/2 mice. The most notable changes were evident in resistance and elastance spectra and baseline lung function, and in lung responsiveness to changes in positive endexpiratory pressure. These data demonstrate that a loss of Sftpd is associated with prolonged lung injury, oxidative stress, and macrophage accumulation and activation in response to ozone, and with more extensive functional changes consistent with the loss of parenchymal integrity. Keywords: ozone; surfactant protein-D; macrophages; iNOS; lung functionOzone is a ubiquitous urban air pollutant generated as a component of photochemical smog. Inhaled ozone causes ozonation and the peroxidation of proteins and lipids in the epithelial lining fluid layer of the lung, resulting in the production of oxidized proteins, aldehydes, and free radicals, which can damage surrounding tissue (1, 2). This is accompanied by an accumulation of activated macrophages in the lung and the production of additional cytotoxic and proinflammatory mediators, including reactive oxygen and reactive nitrogen species (ROS and RNS, respectively) that contribute to tissue injury (3). Airway and tissue mechanics are also altered after ozone exposure. Thus, in humans, ozone inhalation leads to a deterioration of pulmonary function, as measured by decreases in respiratory frequency, forced expiratory volume in 1 second, and forced vital capacity, and increases in airway resistance (1,4,5). Ozone has been shown to exacerbate asthma and increase airway hyperreactivity (5, 6), and to contribute to increased morbidity and mortality in patients with chronic obstructive pulmonary disease (COPD) (7,8). Similar alterations in lung function and increases in sensitivity to ozone have b...

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Noninvasive and Invasive Pulmonary Function in Mouse Models of Obstructive and Restrictive Respiratory Diseases

Cited by 288 publications

References 43 publications

Adenosine A2B Receptor and Hyaluronan Modulate Pulmonary Hypertension Associated with Chronic Obstructive Pulmonary Disease

Adenosine A2B Receptor and Hyaluronan Modulate Pulmonary Hypertension Associated with Chronic Obstructive Pulmonary Disease

SIRT1 protects against emphysema via FOXO3-mediated reduction of premature senescence in mice

Prolonged Injury and Altered Lung Function after Ozone Inhalation in Mice with Chronic Lung Inflammation

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