Chemokines mediate ethanol-induced exacerbations of murine cockroach allergen asthma

Abstract

SummaryAsthma imposes considerable patient and economic burdens, with the most severe cases causing the greatest affliction. Identifying stimuli that worsen asthma severity is an essential step to controlling both disease morbidity and the lessening economic impact. This study provides the first mechanistic investigation into how acute ethanol exposure will increase asthma severity in a murine model of mild cockroach allergen (CRA)-induced asthma. Outbred mice were sensitized to induce mild allergic asthma, with intratracheal CRA exposures on days 0 and 14. On day 21 mice were gavaged with water or 32% ethanol, and the third allergen exposure was given 30 min post-gavage. Asthmatic responses were measured at several time-points up to 42 h after the third allergen challenge. Ethanol-gavaged mice showed increased asthma severity within 90 min post-allergen challenge, with exacerbations lasting for 24 h. Ethanol caused greater airways obstruction, including an eightfold increase in epithelial cell mucin and increased mucus plugs, resulting in a 50% reduction in bronchiole patency. Ethanol gavage also induced significant increases in airways hyperreactivity. While T helper type 1 (Th1) and Th2 cytokines were not altered by ethanol gavage, pulmonary neutrophil and eosinophil recruitment were augmented. This increase was associated with increased chemokine production. Administration 2 h prior to ethanol gavage of a neutralizing antibody cocktail to keratinocyte-derived chemokine, macrophage inflammatory protein-2, eotaxin-1 and eotaxin-2 prevented ethanol-induced eosinophil recruitment and airways hyperreactivity. These data provide evidence that acute alcohol exposure immediately prior to a mild allergen-triggered asthmatic episode will exacerbate asthma severity mediated by increased production of chemokines.

Crucial role of OX40/OX40L signaling in a murine model of asthma

“…Inflammatory responses are important factors for asthma-induced lung injury ( 55 – 57 ). During the acute pathological process, inflammatory cells (including neutrophils and macrophages) are recruited into lung lesions, where they are induced to secret pro-inflammatory cytokines to further accelerate inflammatory responses and promote asthma ( 58 ). Therefore, effective blocking or inhibiting of the inflammatory responses may be a fundamental treatment strategy for asthma.…”

Phospholipase Cε, an Effector of Ras and Rap Small GTPases, Is Required for Airway Inflammatory Response in a Mouse Model of Bronchial Asthma

“…This OVA-challenge-induced cytokine production was highly associated with the PLCε genotype. Because both Ccl2 and Cxcl2 were reported to have a role in induction of AHR and chemoattraction of leukocyte in a mouse model of OVA-induced asthma [37] – [39] , reduced production of these cytokines in bronchial epithelial cells may contribute to the alleviation of asthmatic phenotypes observed in PLCε ΔX/ΔX mice. In Th2-cell-mediated allergic asthma, many types of cells, which include not only bronchial epithelial cells but also leukocytes accumulated at the site of inflammation and other structural cells like fibroblasts, produce a variety of pro-inflammatory molecules.…”

Elevated CXCL14 in Induced Sputum Was Associated with Eosinophilic Inflammation and Airway Obstruction in Patients with Asthma

“…An important molecular mechanism of asthma airway inflammatory pathogenesis is type 2 inflammation [4], and numerous molecules have been reported to be involved in airway inflammatory pathogenesis in asthma [5][6][7][8]. In the pathogenesis of asthma, chemokines, a group of low molecular weight (mostly 8-10 kDa) polypeptides, play a major role in the recruitment and invasion of airway inflammatory cells [9][10][11][12] and are reported to be one of the main stimuli that activate signaling pathways in the epithelial inflammatory reactions in asthma [13][14][15].…”