Cigarette smoke exposure is the major cause of chronic obstructive pulmonary disease (COPD). However, only a minority of smokers develop significant COPD, and patients with asthma or asthma-like airway hyperresponsiveness or eosinophilia experience accelerated loss of lung function after cigarette smoke exposure. Pulmonary inflammation is a characteristic feature of lungs from patients with COPD. Surprisingly, the mediators of this inflammation and their contributions to the pathogenesis and varied natural history of COPD are not well defined. Here we show that IL-13, a critical cytokine in asthma, causes emphysema with enhanced lung volumes and compliance, mucus metaplasia, and inflammation, when inducibly overexpressed in the adult murine lung. MMP-2, -9, -12, -13, and -14 and cathepsins B, S, L, H, and K were induced by IL-13 in this setting. In addition, treatment with MMP or cysteine proteinase antagonists significantly decreased the emphysema and inflammation, but not the mucus in these animals. These studies demonstrate that IL-13 is a potent stimulator of MMP and cathepsin-based proteolytic pathways in the lung. They also demonstrate that IL-13 causes emphysema via a MMP-and cathepsin-dependent mechanism(s) and highlight common mechanisms that may underlie COPD and asthma. in proteases and/or reduction in pulmonary antiproteases (1). Inflammation, characterized by increased numbers of macrophages, lymphocytes, neutrophils, and/or eosinophils is a characteristic feature of lungs from patients with COPD (1,(14)(15)(16)(17)(18)(19). However, the nature of the mediators involved in this inflammation and the ability of these mediators to generate the emphysema and mucus changes, protease/antiprotease alterations, and varied natural history of COPD have not been investigated.Because Th2-dominated inflammation underlies the pathogenesis of asthma and generates AHR and eosinophilia (20-22), we hypothesized that Th2 cytokines can also activate proteolytic pathways that could contribute to the pathogenesis of COPD. To test this hypothesis, we used an inducible overexpression transgenic modeling system to target IL-13, a Th2 cytokine that is strongly implicated in the pathogenesis of asthma and causes AHR and eosinophilia (20,23), to the adult murine lung. These studies demonstrate that IL-13 causes a phenotype that mirrors human COPD including emphysema with enhanced lung volumes and pulmonary compliance; mucus metaplasia; and macrophage-, lymphocyte-, and eosinophil-rich inflammation. They also define the MMP and cathepsin abnormalities that generate the emphysema and demonstrate the efficacy of proteolytic blockade in ameliorating this response. MethodsTransgenic mice. These experiments were undertaken with CC10-rtTA-IL-13 mice in which the Clara cell 10-kDa (CC10) protein promoter and two transgenic constructs target IL-13 to the murine lung in an externally regulatable fashion. The CC10-rtTA transgenic system and the constructs that were used have been described previously by our laboratory (24). Construct 1,...

Emergence of SARS-CoV-2 causing COVID-19 has resulted in hundreds of thousands of deaths. In search for key targets of effective therapeutics, robust animal models mimicking COVID-19 in humans are urgently needed. Here, we show that Syrian hamsters, in contrast to mice, are highly permissive to SARS-CoV-2 and develop bronchopneumonia and strong inflammatory responses in the lungs with neutrophil infiltration and edema, further confirmed as consolidations visualized by micro-CT alike in clinical practice. Moreover, we identify an exuberant innate immune response as key player in pathogenesis, in which STAT2 signaling plays a dual role, driving severe lung injury on the one hand, yet restricting systemic virus dissemination on the other. Our results reveal the importance of STAT2-dependent interferon responses in the pathogenesis and virus control during SARS-CoV-2 infection and may help rationalizing new strategies for the treatment of COVID-19 patients.

The Syrian hamster is highly susceptible to SARS-CoV-2 making it an ideal infection model for COVID-19 countermeasure development.

Chronic inflammation containing CD8 ϩ lymphocytes, neutrophils, and macrophages, and pulmonary emphysema coexist in lungs from patients with chronic obstructive pulmonary disease. Although this inflammatory response is believed to cause the remodeling that is seen in these tissues, the mechanism(s) by which inflammation causes emphysema have not been defined. Here we demonstrate that interferon ␥ (IFN-␥ ), a prominent product of CD8 ϩ cells, causes emphysema with alveolar enlargement, enhanced lung volumes, enhanced pulmonary compliance, and macrophage-and neutrophil-rich inflammation when inducibly targeted, in a transgenic fashion, to the adult murine lung. Prominent protease and antiprotease alterations were also noted in these mice. They included the induction and activation of matrix metalloproteinase (MMP)-12 and cathepsins B, H, D, S, and L, the elaboration of MMP-9, and the selective inhibition of secretory leukocyte proteinase inhibitor. IFN-␥ causes emphysema and alterations in pulmonary protease/antiprotease balance when expressed in pulmonary tissues.

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