• Am. J. Respir. Crit. Care Med. · Feb 2014

    Deficiency of MDA5 Results in Exacerbated Chronic Post-Viral Lung Inflammation.

    • Won-Keun Kim, Deepika Jain, Melissa D Sánchez, Cynthia J Koziol-White, Krystal Matthews, Moyar Q Ge, Angela Haczku, Reynold A Panettieri, Matthew B Frieman, and Carolina B López.
    • 1 Department of Pathobiology, School of Veterinary Medicine, and.
    • Am. J. Respir. Crit. Care Med. 2014 Feb 15; 189 (4): 437-48.

    RationaleRespiratory viral infections can result in the establishment of chronic lung diseases. Understanding the early innate immune mechanisms that participate in the development of chronic postviral lung disease may reveal new targets for therapeutic intervention. The intracellular viral sensor protein melanoma differentiation-associated protein 5 (MDA5) sustains the acute immune response to Sendai virus, a mouse pathogen that causes chronic lung inflammation, but its role in the development of postviral chronic lung disease is unknown.ObjectivesTo establish the role of MDA5 in the development of chronic lung disease.MethodsMDA5-deficient or control mice were infected with Sendai virus. The acute inflammatory response was evaluated by profiling chemokine and cytokine expression and by characterizing the composition of the cellular infiltrate. The impact of MDA5 on chronic lung pathology and function was evaluated through histological studies, degree of oxygen saturation, and responsiveness to carbachol.Measurements And Main ResultsMDA5 deficiency resulted in normal virus replication and in a distinct profile of chemokines and cytokines that associated with acute lung neutropenia and enhanced accumulation of alternatively activated macrophages. Diminished expression of neutrophil-recruiting chemokines was also observed in cells infected with influenza virus, suggesting a key role of MDA5 in driving the early accumulation of neutrophils at the infection site. The biased acute inflammatory response of MDA5-deficient mice led to an enhanced chronic lung inflammation, epithelial cell hyperplasia, airway hyperreactivity, and diminished blood oxygen saturation.ConclusionsMDA5 modulates the development of chronic lung inflammation by regulating the early inflammatory response in the lung.

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