Article ; Online: Deficiency of melanoma differentiation-associated protein 5 results in exacerbated chronic postviral lung inflammation.
American journal of respiratory and critical care medicine
2014 Volume 189, Issue 4, Page(s) 437–448
Abstract: ... 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 ... in a distinct profile of chemokines and cytokines that associated with acute lung neutropenia and enhanced ...
| Abstract | Rationale: Respiratory 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. Objectives: To establish the role of MDA5 in the development of chronic lung disease. Methods: MDA5-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 results: MDA5 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. Conclusions: MDA5 modulates the development of chronic lung inflammation by regulating the early inflammatory response in the lung. |
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| MeSH term(s) | Animals ; Biomarkers/metabolism ; Bronchoalveolar Lavage Fluid/chemistry ; Chemokines/metabolism ; Chronic Disease ; Cytokines/metabolism ; DEAD-box RNA Helicases/deficiency ; Flow Cytometry ; Immunity, Innate ; Interferon-Induced Helicase, IFIH1 ; Lung/enzymology ; Lung/immunology ; Lung/metabolism ; Lung/pathology ; Mice ; Mice, Inbred C57BL ; Pneumonia, Viral/enzymology ; Pneumonia, Viral/immunology ; Pneumonia, Viral/pathology ; Real-Time Polymerase Chain Reaction ; Respirovirus Infections/enzymology ; Respirovirus Infections/immunology ; Respirovirus Infections/pathology ; Sendai virus | |||||
| Chemical Substances | Biomarkers ; Chemokines ; Cytokines ; Ifih1 protein, mouse (EC 3.6.1.-) ; DEAD-box RNA Helicases (EC 3.6.4.13) ; Interferon-Induced Helicase, IFIH1 (EC 3.6.4.13) | |||||
| Keywords | covid19 | |||||
| Language | English | |||||
| Publishing date | 2014-02-19 | |||||
| Publishing country | United States | |||||
| Document type | Journal Article ; Research Support, N.I.H., Extramural | |||||
| ZDB-ID | 1180953-x | |||||
| ISSN | 1535-4970 ; 0003-0805 ; 1073-449X | |||||
| ISSN (online) | 1535-4970 | |||||
| ISSN | 0003-0805 ; 1073-449X | |||||
| DOI | 10.1164/rccm.201307-1338OC | |||||
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| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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