β1-integrins shedding in a guinea-pig model of chronic asthma with remodelled airways

A hallmark of airway remodelling in asthma is subepithelial fibrosis, but its relation with airway dysfunction is still controversial. To describe airway functional abnormalities and subepithelial remodelling induced by repetitive antigenic challenges. Nine inhaled antigenic challenges were applied every 10 days to guinea-pigs sensitized to ovalbumin (OVA). Antigen-induced airway hyperresponsiveness (AI-AHR) to histamine and its immunohistopathological relationship was evaluated at the first, third and ninth OVA challenges. From the first challenge on, OVA induced acute transient bronchoobstruction followed by development of AI-AHR. A progressive rise in baseline Penh (a bronchoobstruction index) and granulocyte airway infiltration was also observed. After the ninth OVA challenge, the amount of extracellular matrix in the subepithelial region (SER) of bronchi and bronchioles was increased. Immunohistochemistry analysis showed that this SER fibrosis was associated to beta 1-integrin subunit overexpression, even in acellular areas. Immunoelectronmicroscopy corroborated the location of beta 1-integrin in extracellular matrix, essentially in types l and II collagen fibres. Presence of alpha 1- and alpha 2-integrin subunits in these areas was also corroborated. AI-AHR was correlated with degree of SER increment, cell infiltration, and beta 1-integrin expression. Our data suggested that beta 1-integrin shedding produced by repetitive allergen challenges in guinea-pigs was associated with collagen deposition in SER of bronchi and bronchioles, along with inflammatory cells infiltration and AI-AHR development.