Roberta Goncalves Marangoni1, Benjamin D Korman2, Edwin R Parra3, Ana Paula P Velosa4, Hermes V Barbeiro5, Vanessa Martins3, Angela B G Dos Santos3, Francisco Soriano5, Walcy R Teodoro4, Pedro Leme Silva6, Warren Tourtellotte7, Vera L Capelozzi3, John Varga8, Natalino H Yoshinari4. 1. Rheumatology Division, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brazil; Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; Division of Allergy, Immunology and Rheumatology, University of Rochester Medical Center, Rochester, NY, USA. Electronic address: Roberta_Goncalvesmarangoni@urmc.rochester.edu. 2. Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; Division of Allergy, Immunology and Rheumatology, University of Rochester Medical Center, Rochester, NY, USA. 3. Department of Translational Molecular Pathology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA. 4. Rheumatology Division, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brazil. 5. Clinical Laboratory in Emergency Medicine, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brazil. 6. Laboratory of Pulmonary Investigation, Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Brazil. 7. Department of Pathology, Neurology and Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA. 8. Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Abstract
OBJECTIVE: The pulmonary vascular remodeling in systemic sclerosis (SSc) is poorly understood and animal models are lacking. Type V collagen (COLV) is elevated in SSc and is implicated in the pathogenesis, and immunization with human COLV induces SSc-like skin and lung changes in rabbits and mice. Here we tested the hypothesis that COLV immunization will induce pathological and functional changes that phenocopy SSc-associated pulmonary vascular disease. METHODS: Pulmonary vascular changes in rabbits immunized with human COLV were extensively characterized by a combination of histology, electron microscopy and immunohistochemistry. Physiologic changes induced by COLV in explanted pulmonary artery rings were evaluated. The pattern of histopathologic alterations and gene expression induced in immunized rabbits were compared to those in SSc patients. RESULTS: COLV immunization was accompanied by striking pulmonary vascular abnormalities, characterized by reduced capillary density, perivascular inflammation, endothelial cell injury and collagen accumulation, that closely phenocopy changes seen in SSc patients. Moreover, pulmonary arteries from immunized rabbits showed impaired ex vivo vascular relaxation. Expression of COL5A2 was significantly increased in the lungs from immunized rabbits (p = 0.02), as well as in patients with SSc (P = 0.02). CONCLUSION: COLV immunity in rabbits is associated with marked vascular remodeling in the lung that phenocopies early-stage human SSc-associated pulmonary vascular disease. COLV immunization therefore represents a novel approach to model SSc pulmonary vascular pathology. Moreover, our findings suggest that COLV might represent a novel pathogenic autoantigen in SSc and future studies with the present model should be developed for possible association with PAH.
OBJECTIVE: The pulmonary vascular remodeling in systemic sclerosis (SSc) is poorly understood and animal models are lacking. Type V collagen (COLV) is elevated in SSc and is implicated in the pathogenesis, and immunization with human COLV induces SSc-like skin and lung changes in rabbits and mice. Here we tested the hypothesis that COLV immunization will induce pathological and functional changes that phenocopy SSc-associated pulmonary vascular disease. METHODS: Pulmonary vascular changes in rabbits immunized with human COLV were extensively characterized by a combination of histology, electron microscopy and immunohistochemistry. Physiologic changes induced by COLV in explanted pulmonary artery rings were evaluated. The pattern of histopathologic alterations and gene expression induced in immunized rabbits were compared to those in SSc patients. RESULTS: COLV immunization was accompanied by striking pulmonary vascular abnormalities, characterized by reduced capillary density, perivascular inflammation, endothelial cell injury and collagen accumulation, that closely phenocopy changes seen in SSc patients. Moreover, pulmonary arteries from immunized rabbits showed impaired ex vivo vascular relaxation. Expression of COL5A2 was significantly increased in the lungs from immunized rabbits (p = 0.02), as well as in patients with SSc (P = 0.02). CONCLUSION: COLV immunity in rabbits is associated with marked vascular remodeling in the lung that phenocopies early-stage human SSc-associated pulmonary vascular disease. COLV immunization therefore represents a novel approach to model SSc pulmonary vascular pathology. Moreover, our findings suggest that COLV might represent a novel pathogenic autoantigen in SSc and future studies with the present model should be developed for possible association with PAH.