Targeted HAS2 expression lessens airway responsiveness in chronic murine allergic airway disease

Hyaluronan (HA), a major component of the extracellular matrix, is secreted by airway structural cells. Airway fibroblasts in allergic asthma secrete elevated levels ofHAin association with increasedHA synthase 2 (HAS2) expression. Thus, we hypothesized that HA accumulation in the airway wall may contribute to airway remodeling and hyperresponsiveness in allergic airways disease. To examine this hypothesis, transgenic mice in which the a-smooth muscle actin (a-SMA) promoter drives HAS2 expression were generated. Mixed male and female a-SMA-HAS2 mice (HAS21 mice, n = 16; HAS22 mice, n = 13) were sensitized via intraperitoneal injection and then chronically challenged with aerosolized ovalbumin (OVA) for 6 weeks. To test airway responsiveness, increasing doses of methacholine were delivered intravenously and airway resistance was measured using the forced oscillation technique. HA, cytokines, and cell types were analyzed in bronchoalveolar lavage fluid, serum, and whole lung homogenates. Lung sections were stained using antibodies specific for HA-binding protein (HABP) and a-SMA, as well as Masson's trichrome stain. Staining of lung tissue demonstrated significantly increased peribronchial HA, a-SMA, and collagen deposition in OVA-challenged a-SMA-HAS21 mice compared with a-SMA-HAS22 mice. Unexpectedly, OVA-challenged a-SMA-HAS21 mice displayed significantly reduced airway responsiveness to methacholine compared with similarly treated a-SMA-HAS22 mice. The total numbers of inflammatory cell types in the bronchoalveolar lavage fluid did not differ significantly between OVA-challenged a-SMA-HAS21 mice and a-SMA-HAS22 mice. We conclude that allergen-challenged mice that overexpress HAS2 in myofibroblasts and smooth muscle cells develop increased airway fibrosis, which lessens airway hyperresponsiveness to bronchoconstrictors.