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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- "In contrast to adiponectin, elevated levels of the proinflammatory hormone leptin are reported to be crucial in connecting obesity to allergic airway inflammation (Shore et al., 2005). Airway hyper-responsiveness and inflammation were both enhanced in ob/ob and db/db mice (Shore et al., 2003; Rivera-Sanchez et al., 2004; Lu et al., 2006), as well as in carboxypeptidase E mutant fat mice exposed to ozone (Johnston et al., 2006). Higher leptin (and lower adiponectin) levels in serum of obese mice have been found in our study, reinforcing the suitability of this murine model to further our understanding of the pathophysiology of asthma in human obesity. "
ABSTRACT: Obesity is associated with deterioration in asthma outcomes. Although airways eosinophil accumulation is characteristic of lung allergic diseases, little is known about the influence of obesity on the allergic eosinophil trafficking from bone marrow to lung tissues, and recruitment to airways lumen. Here, we have assessed the effects of diet-induced obesity on allergic eosinophilic inflammation in mice, examining eosinophil trafficking from bone marrow to airways, and production of T(H)1/T(H)2 cytokines. C57BL/6 mice fed for 10 weeks with standard chow or high-fat diet were sensitized and challenged with ovalbumin. At 24-96 h post-ovalbumin challenge, bronchoalveolar lavage (BAL) fluid, lung tissue and bone marrow were examined. The high-fat-fed mice exhibited increased body weight and epididymal fat, glucose intolerance and alterations in lipid profile compared with the lean mice. Obesity markedly elevated serum leptin and lowered adiponectin levels. Ovalbumin challenge in obese mice promoted a markedly higher eosinophil accumulation in bone marrow and connective tissue surrounding the bronchial and bronchiolar segments. Eosinophil number in BAL fluid of obese mice was lower at 24 and 48 h. Levels of interleukin (IL)-5, eotaxin, tumour necrosis factor-alpha and IL-10 in BAL fluid of obese mice were significantly higher than in lean mice. Diet-induced obesity enhanced eosinophil trafficking from bone marrow to lung tissues, and delayed their transit through the airway epithelium into the airway lumen. Consequently, eosinophils remain longer in lung peribronchiolar segments due to overproduction of T(H)1/T(H)2 cytokines and chemokines.British Journal of Pharmacology 02/2010; 159(3):617-25. DOI:10.1111/j.1476-5381.2009.00560.x · 4.99 Impact Factor
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- "Moreover, transgenic mice lacking nitric oxide synthase II (NOSII) or over expressing superoxide dismutase are protected from ozone toxicity (Fakhrzadeh et al., 2002; Fakhrzadeh et al., 2004a). TNFα expression has also been reported to be upregulated in mouse lung following ozone inhalation (Cho et al., 2001; Fakhrzadeh et al., 2004b; Lu et al., 2006). "
ABSTRACT: Alveolar macrophages (AM) and inflammatory mediators including nitric oxide and peroxynitrite contribute to ozone-induced lung injury. The generation of these mediators is regulated, in part, by the transcription factor NF-kappaB. We previously demonstrated a critical role for NF-kappaB p50 in ozone-induced injury. In the present studies mechanisms regulating NF-kappaB activation in the lung after ozone inhalation were analyzed. Treatment of wild type (WT) mice with ozone (0.8 ppm, 3 h) resulted in a rapid increase in NF-kappaB binding activity in AM, which persisted for at least 12 h. This was not evident in mice lacking TNFalpha which are protected from ozone-induced injury; there was also no evidence of nitric oxide or peroxynitrite production in lungs from these animals. These data demonstrate that TNFalpha plays a role in NF-kappaB activation and toxicity. TNFalpha signaling involves PI-3-kinase (PI3K)/protein kinase B (PKB), and p44/42 MAP kinase (MAPK) which are important in NF-kappaB activation. Ozone Inhalation resulted in rapid and transient increases in p44/42 MAPK and PI3K/PKB in AM from WT mice, which was evident immediately after exposure. Caveolin-1, a transmembrane protein that negatively regulates PI3K/PKB and p44/42 MAPK signaling, was downregulated in AM from WT mice after ozone exposure. In contrast, ozone had no effect on caveolin-1, PI3K/PKB or p44/42 MAPK expression in AM from TNFalpha knockout mice. These data, together with our findings that TNFalpha suppressed caveolin-1 expression in cultured AM, suggest that TNFalpha and downstream signaling mediate activation of NF-kappaB and the regulation of inflammatory genes important in ozone toxicity, and that this process is linked to caveolin-1.Toxicology and Applied Pharmacology 04/2008; 227(3):380-9. DOI:10.1016/j.taap.2007.11.012 · 3.63 Impact Factor