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 of HA in association with increased HA 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 α-smooth muscle actin (α-SMA) promoter drives HAS2 expression were generated. Mixed male and female α-SMA-HAS2 mice (HAS2+ mice, n = 16; HAS2- 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 α-SMA, as well as Masson's trichrome stain. Staining of lung tissue demonstrated significantly increased peribronchial HA, α-SMA, and collagen deposition in OVA-challenged α-SMA-HAS2+ mice compared with α-SMA-HAS2- mice. Unexpectedly, OVA-challenged α-SMA-HAS2+ mice displayed significantly reduced airway responsiveness to methacholine compared with similarly treated α-SMA-HAS2- mice. The total numbers of inflammatory cell types in the bronchoalveolar lavage fluid did not differ significantly between OVA-challenged α-SMA-HAS2+ mice and α-SMA-HAS2- 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.

Genetic sex and the volumes of the caudate-putamen, nucleus accumbens core and shell: original data and a review.

Sex differences are widespread across vertebrate nervous systems. Such differences are sometimes reflected in the neural substrate via neuroanatomical differences in brain region volume. One brain region that displays sex differences in its associated functions and pathologies is the striatum, including the caudate-putamen (dorsal striatum), nucleus accumbens core and shell (ventral striatum). The extent to which these differences can be attributed to alterations in volume is unclear. We thus tested whether the volumes of the caudate-putamen, nucleus accumbens core, and nucleus accumbens shell differed by region, sex, and hemisphere in adult Sprague-Dawley rats. As a positive control for detecting sex differences in brain region volume, we measured the sexually dimorphic nucleus of the medial preoptic area (SDN-POA). As expected, SDN-POA volume was larger in males than in females. No sex differences were detected in the volumes of the caudate-putamen, nucleus accumbens core or shell. Nucleus accumbens core volume was larger in the right than left hemisphere across males and females. These findings complement previous reports of lateralized nucleus accumbens volume in humans, and suggest that this may possibly be driven via hemispheric differences in nucleus accumbens core volume. In contrast, striatal sex differences seem to be mediated by factors other than striatal region volume. This conclusion is presented within the context of a detailed review of studies addressing sex differences and similarities in striatal neuroanatomy.