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.
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.
Pathol Res Pract. 2021 Apr;220:153382. doi: 10.1016/j.prp.2021.153382. Epub 2021 Feb 19.
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.
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.
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).
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.
系统性硬化症（SSc）中的肺血管重构机制尚不清楚，且缺乏动物模型。COL5A2 在 SSc 中升高，并与发病机制有关，而用 COL5A2 免疫兔子和小鼠可诱导出类似 SSc 的皮肤和肺部改变。本研究旨在验证 COL5A2 免疫是否会引起病理和功能改变，从而模拟 SSc 相关的肺血管疾病。
通过组织学、电子显微镜和免疫组织化学相结合的方法，对 COL5A2 免疫兔子的肺血管变化进行了广泛的特征描述。评估了 COL5A2 对离体肺动脉环引起的生理变化。将免疫兔子引起的组织病理学改变和基因表达模式与 SSc 患者进行了比较。
COL5A2 免疫后，肺部血管出现明显异常，表现为毛细血管密度降低、血管周围炎症、内皮细胞损伤和胶原堆积，这些改变与 SSc 患者的改变非常相似。此外，免疫兔子的肺动脉在离体状态下的血管舒张功能受损。免疫兔子的肺部 COL5A2 表达显著增加（p = 0.02），与 SSc 患者的表达增加一致（P = 0.02）。
COL5A2 免疫在兔子中可引起肺部明显的血管重构，模拟人类 SSc 早期的肺血管疾病。因此，COL5A2 免疫为 SSc 肺血管病理学模型提供了一种新方法。此外，我们的研究结果表明，COL5A2 可能是 SSc 中的一种新的致病性自身抗原，未来应使用该模型进行进一步研究，以探讨其与 PAH 的相关性。
