Allergy 2018 : Obesity enhances allergen-induced airway inflammation in murine model of asthma - Rehab Bagadood - Cordula Stover and Yassine Amrani University of Leicester

Abstract

Asthma is a chronic inflammatory disease of the lungs1 affecting millions of people worldwide2. Obesity, on the other hand is considered as a low grade systemic inflammation that affects large number of individuals3. It is important to note that obesity has a significant impact on asthmatic patients as obese patients are mostly suffering from severe symptoms, frequent exacerbation, poor quality of life and poor response to anti-inflammatory therapies including corticosteroids4,5, although the underlying mechanisms are still unknown. We here investigated whether obesity affects pro-asthmatic changes in the lung and immune cells in a murine model of allergic asthma. Methodology: Splenocytes were isolated from ovalbumin (or saline as control) sensitized and challenged C57BL/6 mice that were fed with either low (LFD) or high-fat (HFD) diets. These splenocytes were treated with (1mg/ml ovalbumin) in the presence of dexamethasone and production of different cytokines was measured using ELISA. Inflammatory cytokines levels were also assessed in bronchoalveoral lavage fluids. To score the degree of inflammation and mucus secretion in the airways, mice lung sections were stained with haematoxylin & eosin (HE P<0.0001 and P=0.01 respectively) when compared to that in cells from LFD-fed group. Interestingly, dexamethasone failed to inhibit the production of IL-6 by splenocytes from ovalbumin-challenge HFD-fed mice compared to LFD mice. Ovalbumin-challenged obese mice exhibit significant IL-6 secretion into BALF (P<0.05). H&E and PAS stains showed high levels of inflammatory cell infiltration and mucus secretion in the airways of ovalbumin-challenged mice. More importantly, HFD significantly increased lung inflammation in various compartments including peri-vascular, peri-bronchial and parenchyma areas in ovalbumin-challenged mice. Conclusion and significance: HFD exacerbates allergen responses in vivo and dexamethasone sensitivity in vitro in cultured-splenocytes. Obesity induced by HFD augments allergen-induced airway inflammation possibly as a consequence of increased infiltration of immune cells in the lungs and release of pro-inflammatory cytokines. Asthma is a chronic inflammatory disease of the lungs affecting millions of people worldwide. Obesity, on the other hand is considered as a low-grade systemic inflammation that affects large number of individuals. It is important to note that obesity has a significant impact on asthmatic patients as obese patients are mostly suffering from severe symptoms, frequent exacerbation, poor quality of life and poor response to anti-inflammatory therapies including corticosteroids, although the underlying mechanisms are still unknown. We here investigated whether obesity affects pro-asthmatic changes in the lung and immune cells in a murine model of allergic asthma. Methodology: Splenocytes were isolated from ovalbumin (or saline as control) sensitized and challenged C57BL/6 mice that were fed with either Low (LFD) or High-Fat (HFD) diets. These splenocytes were treated with (1 mg/ml ovalbumin) in the presence of dexamethasone and production of different cytokines was measured using ELISA. Inflammatory cytokines levels were also assessed in bronchoalveolar lavage fluids. To score the degree of inflammation and mucus secretion in the airways, mice lung sections were stained with Haematoxylin & Eosin (HE P<0.0001 and P=0.01 respectively) when compared to that in cells from LFD-fed group. Interestingly, dexamethasone failed to inhibit the production of IL-6 by splenocytes from ovalbumin-challenge HFD-fed mice compared to LFD mice. Ovalbumin-challenged obese mice exhibit significant IL-6 secretion into BALF (P<0.05). H&E and PAS stains showed high levels of inflammatory cell infiltration and mucus secretion in the airways of ovalbumin-challenged mice. More importantly, HFD significantly increased lung inflammation in various compartments including peri-vascular, peri-bronchial and parenchyma areas in ovalbumin-challenged mice. Conclusion & Significance: HFD exacerbate allergen responses in vivo and dexamethasone sensitivity in vitro in culturedsplenocytes. Obesity induced by HFD augments allergen-induced airway inflammation possibly as a consequence of increased infiltration of immune cells in the lungs and release of pro-inflammatory cytokines. Compared to ovalbumin-challenged lean mice, ovalbumin-challenged obese mice had higher levels of IL-6 into BALF by 79%, greater neutrophilic infiltration (by 35%, P<0.05), and higher histopathological changes specifically in peri-vascular, peri-bronchial and parenchyma areas by 27, 46 and 26%. Mucus secretion and eosinophilic infiltration were not affected. Allergen-induced TNFα and IL-6 production was greater by 37% and 68% and resistant to corticosteroid suppression in cultured splenocytes from obese mice compared to responses in cells from lean mice. Recent Publications 1. Increasedβ2?adrenoceptor phosphorylation in airway smooth muscle in severe asthma: possible role of mast cell?derived growth factors Latifa Chachi, Abdulrahman Alzahrani, Cynthia Koziol-White, Michael Biddle, Rehab Bagadood, Reynold A. Panettieri, Jr., Peter Bradding, and Yassine Amrani