Modeling the influence of vitamin D deficiency on cigarette smoke-induced emphysema

Crane-Godreau, Mardi A.; Black, Candice C.; Giustini, Andrew J.; Dechen, Tenzin; Ryu, Jihan; Jukosky, James A.; Lee, Hong-Kee; Bessette, Katherine; Ratcliffe, Nora R.; Hoopes, P. Jack; Fiering, Steven; Kelly, John; Leiter, James C.

doi:10.3389/fphys.2013.00132

Cited by 22 publications

(21 citation statements)

References 54 publications

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“…It is well known that cigarette smoke exposure could result in COPD and emphysema in animals [28][29][30]. Consistent with these reports, we have also previously reported that cigarette smoke-exposed rats developed COPD/emphysema characterized by enlarged alveoli (increased mean linear intersection) [27].…”

Section: Discussionsupporting

confidence: 79%

“…In the current study, however, cigarette smoke exposure was used to prepare PAH model in rats. Cigarette smoke exposure resulted in not only COPD/emphysema, which has been previously reported by us and other investigators [27][28][29][30], but also pulmonary arteriolar wall remodeling and PAH as demonstrated in the current study. Specifically, here, we report that cigarette smoke lead to increase of mean pulmonary arterial pressure (mPAP), right ventricular hypertrophy index (RVHI), arterial wall thickness (WT%) and wall area (WA%).…”

Section: Discussionsupporting

confidence: 70%

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Effect of Simvastatin on 5-HT and 5-HTT in a Rat Model of Pulmonary Artery Hypertension

Jiang

Yuan

Jia

et al. 2015

Cell Physiol Biochem

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Background/Aims: To investigaterole of serotonin (5-HT) and serotonin transporter (5-HTT) in a rat model of cigarette smoke-induced pulmonary artery hypertension (PAH) and the effect of statins on regulating 5HT and 5-HTT. Methods: A rat model of COPD comorbid with PAH was established by cigarette smoke exposure with or without simvastatin administration. The smoking and the simvastatin plus smoking groups were exposed to cigarette smoke daily, and the latter received simvastatin at 5mg/kg, once a day. After 16 weeks of cigarette smoke exposure, body weight and mean pulmonary arterial pressure (mPAP) were measured, bronchoalveolar lavage (BAL) was performed, and lung tissues and blood samples were collected to determine cardiopulmonary pathology, physiological indices, blood levelof 5-HT and expression of 5-HTT in the lung. Results: In addition to alveolar structural damage (COPD-like injury), chronic cigarette smoke exposure lead to pulmonary artery remodeling and PAH as evidenced by significant elevation of mPAP, RVHI, WT%and WA%. Cigarette smoke exposure resulted in significant reduction in animal body weight, and simvastatin significantly prevented smoke-induced weight loss. The number of inflammatory cells in BALF was dramatically increased in smoke exposed rats, and simvastatin dampened the number of leukocytes, neutrophils, lymphocytes, and macrophages. In addition, circulating 5-HTand expression of 5-HTT in the lung were significantly increased in the smoked rats compared to control rats, and it was significantly reduced by simvastatin. Alteration of BALF inflammatory cells, 5-HT and 5-HTT was significantly correlated with changes of mPAP, RVHI, WT% and WA%. Conclusions: Cigarette smoke exposure could result in not only COPD, but also PAH, which may attribute to the alteration of blood 5-HT and lung tissue 5-HTT. Simvastatin could significantly inhibited 5-HT and 5-HTT expression, and by which mechanism, it may protect animals from development of PAH.

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Section: Discussionsupporting

confidence: 79%

Section: Discussionsupporting

confidence: 70%

Effect of Simvastatin on 5-HT and 5-HTT in a Rat Model of Pulmonary Artery Hypertension

Jiang

Yuan

Jia

et al. 2015

Cell Physiol Biochem

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“…In support of our observations, Sasaki and colleagues showed that female C57BL/6 mice have increased end-expiratory lung volume after 20 weeks of cigarette smoke exposure [16]. Furthermore, total lung capacity was increased in mice exposed to 16 weeks of smoke exposure compared to wild type mice [17]. On the other hand, it is by no means certain that the pathology of smoke exposure in mice will precisely recapitulate that seen in humans.…”

Section: Discussionsupporting

confidence: 73%

Sex-Related Differences in Pulmonary Function following 6 Months of Cigarette Exposure: Implications for Sexual Dimorphism in Mild COPD

et al. 2016

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Female smokers have increased risk of chronic obstructive pulmonary disease (COPD) compared with male smokers who have a similar history of cigarette smoke exposure. We have shown previously that chronic smoke exposure for 6 months leads to increased airway wall remodeling in female C57BL/6 mice compared with male C57BL/6 mice. These differences, however, were not evident in female ovariectomized mice exposed to cigarette smoke. Herein, we report on the pulmonary function test results from the flexiVent system, which was used to determine the potential functional consequences of the histologic changes observed in these mice. We found that tissue damping (G) was increased in female compared to male or ovariectomized female mice after smoke exposure. At low oscillating frequencies, complex input resistance (Zrs) and impedance (Xrs) of the respiratory system was increased and decreased, respectively, in female but not in male or ovariectomized female mice after smoke exposure. Quasistatic pressure-volume curves revealed a reduction in inspiratory capacity in female mice but not in male or ovariectomized female mice after smoke exposure. The remaining lung function measurements including quasistatic compliance were similar amongst all groups. This is the first study characterizing a sexual dimorphism in respiratory functional properties in a mouse model of COPD. These findings demonstrate that increased airway remodeling in female mice following chronic smoke exposure is associated with increased tissue resistance in the peripheral airways. These data may explain the importance of female sex hormones and the increased risk of airway disease in female smokers.

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“…Measures of lung compliance and elastance are usually similar in C57BL/6 wild type (WT) mice exposed to air or CS for 6 months due to the relatively mild emphysema that develops when this strain is exposed to CS (10) (10) , in CS-exposed C57BL/6 strain gene-targeted mice that have a more severe emphysema type than C57BL/6 WT mice (13) , or in CS-exposed mice subjected to environmental changes that render them more susceptible to the effects of CS (14) . This protocol uses a small animal ventilator to measure reductions in the elastic recoil of the lung (increases in quasistatic lung compliance [Cst] and reductions in tissue elastance [H]), PV flow loops, and changes in airway and tissue resistance in anesthetized mice (15,16) .…”

Section: Pulmonary Function Test (Pfts)mentioning

confidence: 99%

Automated Measurement of Pulmonary Emphysema and Small Airway Remodeling in Cigarette Smoke-exposed Mice

Laucho-Contreras

Taylor

Mahadeva

et al. 2015

JoVE

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COPD is projected to be the third most common cause of mortality world-wide by 2020 (1) . Animal models of COPD are used to identify molecules that contribute to the disease process and to test the efficacy of novel therapies for COPD. Researchers use a number of models of COPD employing different species including rodents, guinea-pigs, rabbits, and dogs (2) . However, the most widely-used model is that in which mice are exposed to cigarette smoke. Mice are an especially useful species in which to model COPD because their genome can readily be manipulated to generate animals that are either deficient in, or over-express individual proteins. Studies of gene-targeted mice that have been exposed to cigarette smoke have provided valuable information about the contributions of individual molecules to different lung pathologies in COPD (3)(4)(5) . Most studies have focused on pathways involved in emphysema development which contributes to the airflow obstruction that is characteristic of COPD. However, small airway fibrosis also contributes significantly to airflow obstruction in human COPD patients (6) , but much less is known about the pathogenesis of this lesion in smoke-exposed animals. To address this knowledge gap, this protocol quantifies both emphysema development and small airway fibrosis in smoke-exposed mice. This protocol exposes mice to CS using a whole-body exposure technique, then measures respiratory mechanics in the mice, inflates the lungs of mice to a standard pressure, and fixes the lungs in formalin. The researcher then stains the lung sections with either Gill's stain to measure the mean alveolar chord length (as a readout of emphysema severity) or Masson's trichrome stain to measure deposition of extracellular matrix (ECM) proteins around small airways (as a readout of small airway fibrosis). Studies of the effects of molecular pathways on both of these lung pathologies will lead to a better understanding of the pathogenesis of COPD. Video LinkThe video component of this article can be found at

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Modeling the influence of vitamin D deficiency on cigarette smoke-induced emphysema

Cited by 22 publications

References 54 publications

Effect of Simvastatin on 5-HT and 5-HTT in a Rat Model of Pulmonary Artery Hypertension

Effect of Simvastatin on 5-HT and 5-HTT in a Rat Model of Pulmonary Artery Hypertension

Sex-Related Differences in Pulmonary Function following 6 Months of Cigarette Exposure: Implications for Sexual Dimorphism in Mild COPD

Automated Measurement of Pulmonary Emphysema and Small Airway Remodeling in Cigarette Smoke-exposed Mice

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