Targeted HAS2 Expression Lessens Airway Responsiveness in Chronic Murine Allergic Airway Disease.

Walker, Julia KL

Theriot, Barbara S

Ghio, Michael

Trempus, Carol S

Wong, Jordan E

McQuade, Victoria L

Liang, Jiurong

Jiang, Dianhua

Noble, Paul W

Garantziotis, Stavros

Kraft, Monica

Ingram, Jennifer L

2022-07-01T14:23:56Z

2022-07-01T14:23:56Z

2017-12

2022-07-01T14:23:55Z

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.

1044-1549

1535-4989

https://hdl.handle.net/10161/25432

eng

American Thoracic Society

American journal of respiratory cell and molecular biology

10.1165/rcmb.2017-0095oc

Lung

Myocytes, Smooth Muscle

Animals

Mice, Knockout

Humans

Mice

Asthma

Chronic Disease

Actins

Allergens

Gene Expression Regulation, Enzymologic

Bronchoconstriction

Myofibroblasts

Hyaluronan Synthases

Targeted HAS2 Expression Lessens Airway Responsiveness in Chronic Murine Allergic Airway Disease.

Journal article

Ingram, Jennifer L|0000-0002-5269-8864

702

710

6

Duke

School of Medicine

School of Nursing

Faculty

Staff

Clinical Science Departments

Medicine

Pathology

Surgery

Medicine, Pulmonary, Allergy, and Critical Care Medicine

Surgery, Surgical Sciences

Published

57