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Modeling Epithelial-Effector Cell Crosstalk in the Pathogenesis of Diffuse Parenchymal Lung Disease

Wednesday, May 29, 2019

4:00 PM-5:30 PM

BIOMED Seminar

Modeling Epithelial-Effector Cell Crosstalk in the Pathogenesis of Diffuse Parenchymal Lung Disease

Alessandro Venosa, PhD
Postdoctoral Researcher
Pulmonary, Allergy and Critical Care Division
Perelman School of Medicine
University of Pennsylvania

Epithelial cell dysfunction is postulated as an important component in the pathogenesis of interstitial lung disease (ILD) and could potentially be highly susceptible to air pollutant exposure (e.g., ozone). Mutations in the surfactant protein C (SP-C) gene (SFTPC), an alveolar type II (AT2) cell–restricted protein, have been found in sporadic and familial idiopathic pulmonary fibrosis. Our group has developed a tamoxifen inducible knock-in mouse model of lung fibrosis that expresses a human ILD-associated isoleucine-to-threonine substitution at codon73 (I73T) in the Sftpc (SP-CI73T). The founder line was hypomorphic and, despite constitutive low level expression of SP-CI73T in AT2 cells, develops moderate enlargement of the alveolar septae, AT2 cell hyperplasia, and minor inflammatory cell infiltrate beginning at 16 wk of age and deteriorating with time.

Induction of SftpcI73T mRNA and misprocessed proSP-CI73T protein by tamoxifen results in a more extreme parenchymal phenotype, alveolitis, and increased early mortality. Surviving mice demonstrate aberrant with features of IPF including spatially heterogeneous peripheral fibrosis, increased collagen deposition, AT2 cell hyperplasia, α-SMA–positive cells, and restrictive lung physiology. Population RNAseq of AT2 cells indicates this key cells coordinate sequential recruitment of CCR2+Ly6C+ monocytes, Ly6G+ neutrophils and SiglecF+CD11clo eosinophils, effector cells identified in IPF patients. Genetic and pharmacologic depletion of these effector cells with CCR2ko and intravascular clodronate liposomes, results in reduced inflammatory burden (total BALF and eosinophil counts) and improved survival up to 2wk post SP-CI73T induction. Since aging and environmental exposure represent important factors in the development of chronic interstitial pulmonary disease, we also analyzed the histopathological effects of ozone exposure (0.8 ppm, 3h) on 52wk hypomorphic SP-CI73T mice. Exposure of these mice to ozone revealed enhanced histopathological evidence of alveolar septal disruption, perivascular edema and perivascular and peribronchial immune cells infiltrate, as well as abnormal lymphatic vessels and B220+ B cell dominant bronchoalveolar lymphoid tissue expansion.

Taken together, this clinically relevant preclinical model highlights the role of AT2 cell dysfunction in the initiation and progression of lung injury and remodeling; establishes a link between deleterious pro-inflammatory CCR2+Ly6Chi monocytes and histopathological lung remodeling. Furthermore, we established a platform to test the contribution of environmental air pollutants to the onset and progression of diffuse parenchymal lung diseases.

Alessandro Venosa, PhD, is currently a postdoctoral research fellow in the Pulmonary, Allergy and Critical Care Division at Perelman School of Medicine at the University of Pennsylvania. After receiving his Pharm.D. from the Universita’ degli Studi di Urbino (Italy) in 2009, he moved to the United States and earned a PhD in Toxicology (2015) at Rutgers University where he also participated in several K4-12 and outreach programs and worked as a teaching assistant.

Dr. Venosa received multiple awards for graduate/postdoctoral research and authored 14 publications including recently publication in the Journal of Clinical Investigation and Journal of Immunology establishing a novel murine model of lung fibrosis and the inflammatory responses mediating injury initiation and progression. He served as Chair for a Gordon Research Seminar in Cellular and Molecular Mechanisms of Toxicity, member of the Young Scientist Committee within the Society for Experimental Biology, and postdoctoral representative to the Society of Toxicology including the Toxicology and Exploratory Pathology (2015-17) and Immunotoxicology (current) Specialty Sections.

Contact Information

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