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The Synergistic Interactions of Allergic Lung Inflammation and Intratracheal Cationic Protein

¹ Vermont Lung Center, ² Department of Medicine, and ³ Department of Molecular Physiology and Biophysics, University of Vermont, Burlington, Vermont

Correspondence and requests for reprints should be addressed to Dr. Jason H.T. Bates, Ph.D., HSRF 228, 149 Beaumont Avenue, Burlington, VT 05405-0075. E-mail: jason.h.bates{at}uvm.edu

Rationale: Airways hyperresponsiveness (AHR) is a hallmark feature of asthma, and can be caused by various disparate mechanisms. Mouse models of AHR have been useful for studying these mechanisms in isolation, but such models still typically do not exhibit the same degree of AHR as seen in severe human asthma. We hypothesized that more severe AHR in mice could be achieved by imbuing them with more than one mechanism of AHR.

Objectives: We sought to determine if the airway wall thickening accompanying allergic inflammation and the exaggerated smooth muscle shortening induced by intratracheal cationic protein could act together to produce a severe form of AHR.

Methods: We used the forced oscillation technique to measure methacholine responsiveness in BALB/c mice that had been sensitized and challenged with ovalbumin followed by an intratracheal instillation of poly-L-lysine.

Measurements and Main Results: We found that both ovalbumin and poly-L-lysine treatment alone caused moderate levels of AHR. When the two treatments were combined, however, they synergized in terms of their effect on lung stiffness to an extent that could even be fatal, reflecting a significantly enhanced level of airway closure.

Conclusions: Our results suggest that mechanistic synergy between airway wall thickening and exaggerated smooth muscle shortening produces a more germane mouse model of asthma that may have particular relevance to the pathophysiology of the acute severe asthma exacerbation.

Key Words: airway hyperresponsiveness • methacholine • mouse model • asthma exacerbation

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject The causes of asthma attacks are unknown, despite the evidence that such attacks may simultaneously involve both the lung periphery and the central airways. What This Study Adds to the Field Exaggerated central airway constriction on a background of lung inflammation can cause extreme decrement in lung function, and even death, in mice. This is due to a synergy between smooth muscle shortening and airway wall thickening.

 

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