Obesity increases airway hyperresponsiveness via the TNF-α pathway and treating obesity induces recovery

Abstract

Obesity is a known risk factor for allergic asthma. It has been recognized as a key player in the pathogenesis of several inflammatory disorders via activation of macrophages, which is also vital to the development of allergic asthma. We investigated the mechanism of obesity-related asthma and whether treating obesity through exercise or diet ameliorates the severity of asthma in the obesity-related asthma model. We generated diet-induced obesity (DIO) in C57BL/6 mice by high-fat-feeding and ovalbumin-induced asthma (lean-OVA or DIO-OVA). The DIO-OVA mice were then treated with tumor necrosis factor (TNF)-α neutralizing antibody as a TNF-α blockade or a Cl2MDP-containing liposome to induce an alveolar macrophage deficiency. To treat obesity, the DIO-OVA mice were under dietary restrictions or exercised. The pathophysiological and immunological responses were analyzed. Airway hyperresponsiveness (AHR), serum IgE and TNF-α levels in the lung tissue increased in the DIO-OVA mice compared to the lean-OVA mice. Both the TNF-α blockade and depletion of alveolar macrophages in the DIO-OVA mice decreased AHR compared to the DIO-OVA mice. Treating obesity by exercise or through dietary means also reduced pulmonary TNF-α levels and AHR in the DIO-OVA mice. These results suggest that restoring normal body weight is an appropriate strategy for reducing TNF-α levels, and controlling inflammation may help improve asthma severity and control in obesity-related asthma.

Figure 1. Mouse models in this study.

(a) Scheme of this study. C57BL/6 mice fed HFD for 16 weeks and some of the DIO mice underwent OVA sensitization and challenge (DIO-OVA). Some of the DIO-OVA mice were treated with TNF-α neutralizing antibody for TNF-α blockade or a Cl₂MDP-containing liposome for alveolar macrophage depletion. For the treatment of obesity, the DIO-OVA mice performed voluntary exercise (DIO-OVA-Ex) or underwent dietary restriction (DIO-OVA-N) after 12 weeks of HFD feeding. (b) Body weight and (c) blood glucose tolerance was measured at the end of 16 weeks after HFD feeding. *, Statistical significance to lean mice (p<0.05); ^#, Statistical significance to DIO mice. i.p., intraperitoneal injection; i.n., intranasal injection; TNF, TNF-α neutralizing antibody. Error bars indicated mean±SEM of five mice per group. All data are representative of three independent experiments.

Figure 2. Obesity exacerbates asthmatic symptoms in the asthma model.

(a) AHR, (b) inflammatory cell infiltrations in the BAL fluids, (c) total IgE and (d) OVA-IgE levels in the sera were measured in the asthma model (lean-OVA) and obesity-related asthma model (DIO-OVA). *, Statistical significance to their control group (lean or DIO; p<0.05); ^#, Statistical significance between lean-OVA and DIO-OVA (p<0.05). Error bars indicated mean±SEM of five mice per group. All data are representative of three independent experiments.

Figure 3. Obesity increases TNF-α levels in the asthma model.

TNF-α levels in (a) the bronchoalveolar lavage fluids and (b) the blood sera were measured in the asthma models. The solid lines indicate statistical significance between each group (p<0.05). N.D., not detected. Error bars indicated mean±SEM of five mice per group. All data are representative of three independent experiments.

Figure 4. Depletion of TNF-α or alveolar macrophages attenuate lung dysfunction in the obesity-related asthma model.

(a) Both lean-OVA and DIO-OVA mice were treated with TNF-α blockade antibody or Cl₂MDP for depletion of TNF-α or alveolar macrophages, respectively, and TNF-α levels in the lung homogenates were measured. (b) MCh AHR was measured in the TNF-α or alveolar macrophage depleted DIO-OVA. *, Statistical significance to lean mice (p<0.05); ^#, Statistical significance to DIO mice. TNF, TNF-α neutralizing antibody. Error bars indicated mean±SEM of five mice per group. All data are representative of three independent experiments.

Figure 5. Treating obesity decreases TNF-α levels in the obesity-related asthma model.

DIO mice performed voluntary exercise or consumed a normal chow diet to treat obesity. TNF-α levels in the lung homogenates were measured in the weight-reduced, obesity-related asthma mice. The solid lines indicate statistical significance between each group (p<0.05). Error bars indicated mean±SEM of five mice per group. All data are representative of three independent experiments.

Figure 6. Treating obesity decreases lung dysfunction in the obesity-related asthma model.

DIO mice performed voluntary exercise or consumed a normal chow diet to treat obesity. (a) Airway hyperresponsiveness and (b) inflammatory cell infiltration in the bronchoalveolar lavage fluid were measured in the weight-reduced, obesity-related asthma mice. *, Statistical significance to lean mice (p<0.05); ^#, Statistical significance to DIO mice. DIO-N-OVA, DIO-OVA mice with diet-restriction; DIO-Ex-OVA, DIO-OVA mice with voluntary exercise. Error bars indicated mean±SEM of five mice per group. All data are representative of three independent experiments.