Editors' ChoiceFibrosis

Finding the smoking gun of lung fibrosis after influenza

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Science Translational Medicine  29 Aug 2018:
Vol. 10, Issue 456, eaau8879
DOI: 10.1126/scitranslmed.aau8879

Abstract

A preclinical model of influenza-related lung injury reveals the impact of smoking on tissue repair mechanisms.

A century ago, the 1918 influenza pandemic killed more than 50 million people worldwide. Although we have learned a great deal about it, influenza continues to carry marked morbidity and mortality, primarily due to pneumonia and other respiratory complications, such as adult respiratory distress syndrome. Epidemiological data indicate that smokers are at higher risk for poor outcome after influenza, but the mechanisms of this association are not clear. Furthermore, a subset of chronic obstructive pulmonary disease patients who have frequent exacerbations with respiratory infections subsequently develop a form of interstitial lung disease characterized by fibrotic lung changes.

In a recent study, Lee et al. describe a possible mechanism by which cigarette smoke contributes to aberrant lung tissue repair after influenza infection. Using a preclinical model, the authors initially exposed mice to two weeks of cigarette smoke followed by an intranasal challenge with influenza, with continued smoke exposure afterwards. Control mice either were only infected with influenza or only exposed to cigarette smoke. The authors then investigated the effects of cigarette smoke on the inflammatory and repair phases of the response to influenza. As expected, cigarette smoke was associated with an increased number of inflammatory cells, but they did not observe impaired clearance of the virus. Importantly, during the repair phase, there was an increase in collagen deposition in the lungs. Immunohistochemistry staining for fibroblast specific protein 1 showed that fibroblasts from smoke-exposed mice had increased proliferation and expression of α-smooth muscle actin-positive stress fibers. Cigarette smoke also up-regulated several growth factors in isolated fibroblasts, such as connective tissue growth factor, vascular endothelial growth factor–α (VEGFα), VEGFβ, platelet-derived growth factor–α (PDGFα), and PDGFβ. Transforming growth factor–β (TGFβ), an important profibrotic growth factor, was increased during the repair phase in mice exposed to cigarette smoke, and TGFβ blockade ameliorated the fibrotic responses and improved the recovery from influenza virus infection.

Overall, this preclinical model of influenza infection provides new insights about dysregulation of fibroblasts mediated by cigarette smoke, which impairs lung remodeling. The clinical relevance of these observations needs to be explored in human cohorts with influenza or with interstitial lung diseases associated with smoking, such as desquamative interstitial pneumonia, respiratory bronchiolitis–associated interstitial lung disease, and pulmonary Langerhans cell histiocytosis.

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