Increased pulmonary responses to acute ozone exposure in obese db/db mice
ABSTRACT Epidemiological studies indicate the incidence of asthma is increased in obese and overweight humans. Responses to ozone (O(3)), an asthma trigger, are increased in obese (ob/ob) mice lacking the satiety hormone leptin. The long form of leptin receptor (Ob-R(b)) is required for satiety; mice lacking this receptor (db/db mice) are also substantially obese. Here, wild-type (WT) and db/db mice were exposed to air or O(3) (2 ppm) for 3 h. Airway responsiveness, measured by the forced oscillation technique, was greater in db/db than WT mice after air exposure. O(3)-induced increases in pulmonary resistance and airway responsiveness were also greater in db/db mice. BALF eotaxin, IL-6, KC, and MIP-2 increased 4 h after O(3) exposure and subsided by 24 h, whereas protein and neutrophils continued to increase through 24 h. For each outcome, the effect of O(3) was significantly greater in db/db than WT mice. Previously published results obtained in ob/ob mice were similar except for O(3)-induced neutrophils and MIP-2, which were not different from WT mice. O(3) also induced pulmonary IL-1beta and TNF-alpha mRNA expression in db/db but not ob/ob mice. Leptin was increased in serum of db/db mice, and pulmonary mRNA expression of short form of leptin receptor (Ob-R(a)) was similar in db/db and WT mice. These data confirm obese mice have innate airway hyperresponsiveness and increased pulmonary responses to O(3). Differences between ob/ob mice, which lack leptin, and db/db mice, which lack Ob-R(b) but not Ob-R(a), suggest leptin, acting through Ob-R(a), can modify some pulmonary responses to O(3).
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- "The fact that leptin deficient (ob/ob) and leptin receptor deficient (db/db) mice are hyperresponsive is also supportive of the bronchodilator effect of leptin (Arteaga-Solis et al. 2013; Johnston, et al. 2007; Lu, et al. 2006; Shore, et al. 2003). Leptin and leptin receptor deficiencies also worsen AHR in a murine model of asthma elicited by ozone exposure (Lu et al. 2006; Shore et al. 2003). In addition, infusion of leptin intracerebroventricularly successfully inhibits AHR observed in high fat diet-induced obese mice, ob/ob but not db/db mice, as well as in mice with allergic airway inflammation (Arteaga-Solis et al. 2013). "
ABSTRACT: Asthma is a prevalent respiratory disorder triggered by a variety of inhaled environmental factors, such as allergens, viruses and pollutants. Asthma is characterized by an elevated activation of the smooth muscle surrounding the airways, as well as a propensity of the airways to narrow excessively in response to a spasmogen (i.e. contractile agonist), a feature called airway hyperresponsiveness. The level of airway smooth muscle activation is putatively controlled by mediators released in its vicinity. In asthma, many mediators that affect airway smooth muscle contractility originate from inflammatory cells that are mobilized into the airways, such as eosinophils. However, mounting evidence indicates that mediators released by remote organs can also influence the level of activation of airway smooth muscle, as well as its level of responsiveness to spasmogens and relaxant agonists. These remote mediators are transported through circulating blood to act either directly on airway smooth muscle or indirectly via the nervous system by tuning the level of cholinergic activation of airway smooth muscle. Indeed, mediators generated from a diversity of organs, including the adrenals, pancreas, adipose tissues, gonads, heart, intestines and stomach affect the contractility of airway smooth muscle. Together, these results suggest that, apart from a paracrine mode of regulation, airway smooth muscle is subjected to an endocrine mode of regulation. The results also imply that defects in organs other than the lungs can contribute to asthma symptoms and severity. In this review, I suggest that the endocrine mode of regulation of airway smooth muscle contractility is overlooked.Journal of Endocrinology 06/2014; DOI:10.1530/JOE-14-0220 · 3.59 Impact Factor
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- "However, AHR or eosinophilic inflammation in lung tissue was not augmented by obesity per se. This finding is in contrast with the results of previous studies showing that AHR is a common feature of murine obesity.12,13 In the present study, we used a diet-induced obesity model with C57BL/6J mice. "
ABSTRACT: Purpose Obesity has been suggested to be linked to asthma. However, it is not yet known whether obesity directly leads to airway hyperreactivity (AHR) or obesity-induced airway inflammation associated with asthma. We investigated obesity-related changes in adipokines, AHR, and lung inflammation in a murine model of asthma and obesity. Materials and Methods We developed mouse models of chronic asthma via ovalbumin (OVA)-challenge and of obesity by feeding a high-fat diet, and then performed the methacholine bronchial provocation test, and real-time PCR for leptin, leptin receptor, adiponectin, adiponectin receptor (adipor1 and 2), vascular endothelial growth factor (VEGF), transforming growth factor (TGF) β, and tumor necrosis factor (TNF) α in lung tissue. We also measured cell counts in bronchoalveolar lavage fluid. Results Both obese and lean mice chronically exposed to OVA developed eosinophilic lung inflammation and AHR to methacholine. However, obese mice without OVA challenge did not develop AHR or eosinophilic inflammation in lung tissue. In obese mice, lung mRNA expressions of leptin, leptin receptor, VEGF, TGF, and TNF were enhanced, and adipor1 and 2 expressions were decreased compared to mice in the control group. On the other hand, there were no differences between obese mice with or without OVA challenge. Conclusion Diet-induced mild obesity may not augment AHR or eosinophilic lung inflammation in asthma.Yonsei medical journal 11/2013; 54(6):1430-7. DOI:10.3349/ymj.2013.54.6.1430 · 1.26 Impact Factor
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- "It is the reason why the lymphocytes increased followed by macrophages. However, our results were different from Lu’s reports , which showed that db/db mice exhibited AHR but BALF inflammatory cells were not significantly different from lean mice after air exposure. After challenged with ovalbumin, inflammatory cells from ob/ob mice were increased in the lung tissue to greater extent than wide-type mice, but the extent of increase in BALF was still lower than wild-type mice , . "
ABSTRACT: Background Obesity is a risk factor for the development of certain respiratory diseases, and neonatal overfeeding results in an early onset of obesity in adulthood. However, the influence of neonatal overfeeding on respiratory diseases has rarely been studied. Therefore, this paper is aimed at investigating the effect of neonatal overfeeding on airway responsiveness and inflammation. Methodology/Principal Findings The neonatal overfeeding was induced by reducing litter size to three pups per litter (small litter, SL) in contrast to the normal litter size with ten pups per litter (NL) on postnatal day 3 (P3) in male ICR mice. On P21, mice were weaned to standard chow diet. Airway responsiveness to methacholine was measured either on P21 or P150. Total and classified inflammatory cells in bronchoalveolar lavage fluid (BALF) were counted, lung inflammatory cells were evaluated through staining with hematoxylin & eosin and F4/80 immunohistochemistry; lung fibrosis was evaluated through staining with Masson and α-SAM immunohistochemistry. Leptin levels in serum were measured by RIA; TNF-α levels in serum and BALF were quantified by ELISA; mRNA levels of TNF-α, CTGF and TGF-β1 in lung tissues were measured using real-time PCR. Mice from SL exhibited accelerated body weight gain, impaired glucose tolerance and hyperleptinemia. Enhanced airway responsiveness to methacholine was observed in SL mice on P150, but not on P21. Pulmonary inflammation was evident in SL mice on P150, as reflected by inflammatory cells especially macrophages around bronchi and interstitium. BALF and serum TNF-α levels and lung TNF-α mRNA expression were significantly increased in SL mice on P150. More collagen accumulated surrounding the bronchi on P150; lung mRNA levels of TGF-β1 and CTGF were also increased on P150. Conclusion In addition to inducing a variety of metabolic defects, neonatal overfeeding enhanced lung inflammation, which may lead to airway remodeling and airway hyperresponsiveness in adulthood.PLoS ONE 10/2012; 7(10):e47013. DOI:10.1371/journal.pone.0047013 · 3.23 Impact Factor