title: Hypertrophic airway smooth muscle mass correlates with increased airway responsiveness in a murine model of asthma.
abstract: The increase of airway smooth muscle (ASM) mass in asthma results from hypertrophic and hyperplastic stimuli, and leads to an increase in cellular contractile proteins. However, little evidence correlates the relative contributions of hypertrophic and hyperplastic muscle with functional effects on airway resistance. We performed a ventilator-based assessment of respiratory mechanics and responsiveness to methacholine in a murine model of acute (3-week) ovalbumin (OVA)-induced airway inflammation, compared with a chronic (12-week) model. We correlated functional changes in airways Newtonian resistance (RN), peripheral tissue damping (G), and elastance (H) with the relative contributions of proliferation, hypertrophy, and apoptosis to increased ASM mass. Immunohistochemical analyses of treated (OVA-sensitized and OVA-challenged; OVA/OVA) and control (OVA-sensitized and saline-challenged; OVA/PBS) murine lungs showed an increase in ASM area in chronic, but not acute, OVA/OVA-treated mice that correlated positively with increased airway resistance to methacholine. Acute OVA/OVA-treated ASM exhibited an increase in proliferation with diminished apoptosis, which resolved in the chronic OVA/OVA model. Chronic OVA/OVA-treated ASM exhibited hypertrophy. Distinct temporal differences exist in the response of murine airways to antigenic challenge. We report that ASM proliferation and diminished apoptosis occur during the acute phase, followed by the development of smooth muscle hypertrophy and an increased muscle mass with chronic challenge, that correlate strongly with increased airway Newtonian resistance. The identification of a functionally relevant hypertrophic bronchial muscle mass highlights the possibility of regulating airway muscle hypertrophy as a novel therapeutic target in asthma.
authors: Division of Clinical Sciences, Department of Medicine, University of Toronto, Ontario, Canada.
authors: Pamela J
authors: PJ
authors: Plant
authors: Michelle L
authors: ML
authors: North
authors: Andrew
authors: A
authors: Ward
authors: Michael
authors: M
authors: Ward
authors: Nivedita
authors: N
authors: Khanna
authors: Judy
authors: J
authors: Correa
authors: Jeremy A
authors: JA
authors: Scott
authors: Jane
authors: J
authors: Batt
mesh_terms: D000403:Airway Resistance; D000818:Animals; D017209:Apoptosis / Q000276:immunology; D001249:Asthma / Q000276:immunology / Q000503:physiopathology*; D049109:Cell Proliferation; D004195:Disease Models, Animal; D005260:Female; D006984:Hypertrophy / Q000503:physiopathology; D016210:Methacholine Chloride / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D009130:Muscle, Smooth / Q000187:drug effects / Q000276:immunology / Q000473:pathology*; D010047:Ovalbumin / Q000009:adverse effects / Q000276:immunology; D012130:Respiratory Hypersensitivity / Q000276:immunology / Q000503:physiopathology*
chemical_list: D016210:Methacholine Chloride; D010047:Ovalbumin