Fra-2 transgenic mice as a novel model of pulmonary hypertension associated with systemic sclerosis

Abstract

OBJECTIVE: Systemic sclerosis-associated pulmonary arterial hypertension differs from idiopathic pulmonary arterial hypertension with respect to histopathology, treatment responses and survival. Medical progress on PAH is hampered by the lack of human biosamples and suitable animal models. In this study, the authors evaluated fos-related antigen 2 (Fra-2) transgenic mice as a novel model for systemic sclerosis-associated pulmonary arterial hypertension.METHODS: Lung sections of Fra-2 transgenic (n=12) and wild-type mice (n=6) were analysed at 16 weeks by histology using Dana Point criteria. Cellular and molecular key players were assessed by immunohistochemistry. To test the model's sensitivity to change over treatment, a subgroup of Fra-2 transgenic mice (n=6) was treated with the tyrosine kinase inhibitor nilotinib twice daily 37.5 mg orally from 8 weeks of age.RESULTS: Fra-2 transgenic mice developed severe vascular remodelling of pulmonary arteries and non-specific interstitial pneumonia-like interstitial lung disease resembling human systemic sclerosis-associated pulmonary hypertension. Histological features typical for systemic sclerosis-associated pulmonary arterial hypertension, such as intimal thickening with concentric laminar lesions, medial hypertrophy, perivascular inflammatory infiltrates, adventitial fibrosis, but not pulmonary occlusive venopathy were frequently detected. Platelet-derived growth factor signalling pathways were activated in pulmonary vessels of Fra-2 transgenic compared with wild-type mice. Since treatment with nilotinib strongly prevented the development of proliferative vasculopathy and lung fibrosis, the model proved to be sensitive to treatment.CONCLUSIONS: This study suggests that Fra-2 transgenic mice as an animal model of systemic sclerosis-associated pulmonary arterial hypertension display main characteristic features of the human disease. It therefore allows studying pathophysiological aspects and might serve as a preclinical model for interventional proof-of-concept studies. MethodsLung sections of Fra-2 transgenic (n=12) and wildtype mice (n=6) were analyzed at 16 weeks by histology using Dana Point criteria. Cellular and molecular key players were assessed by immunohistochemistry. To test the model's sensitivity to change over treatment, a subgroup of Fra-2 transgenic mice (n=6) was treated with the tyrosine kinase inhibitor nilotinib at 2x 37.5mg/d p. o. from 8 weeks of age. ResultsFra-2 transgenic mice developed severe vascular remodeling of pulmonary arteries and nonspecific interstitial pneumonia-like interstitial lung disease resembling human systemic sclerosis-associated pulmonary hypertension. Histological features typical for systemic sclerosis-associated pulmonary arterial hypertension such as intimal thickening with concentric laminar lesions, medial hypertrophy, perivascular inflammatory infiltrates, adventitial fibrosis, but not pulmonary occlusive venopathy were frequently detected. Platelet-derived growth factor signaling pathways were activate...

LOXL4 Is Induced by Transforming Growth Factor β1 through Smad and JunB/Fra2 and Contributes to Vascular Matrix Remodeling

“…Fra2 has recently evolved as an extremely interesting factor in the context of vascular ECM remodeling and fibrosis (33)(34)(35)(36). In order to confirm the implication of Fra2 in the upregulation of LOXL4 expression, we performed gain-and loss-of-function experiments.…”

“…Additionally, Fra2 was found to be overexpressed in the dermis of patients with scleroderma, where it has been proposed to play a role in the induction of ECM proteins upon TGF-␤1 stimulation (34,36). Transgenic mice overexpressing Fra2 develop extensive fibrosis in several organs, with the pulmonary tissue being particularly affected, which is initiated as a severe vasculopathy characterized by vascular remodeling and obliteration of pulmonary arteries (35). Based on these observations and our own results in vascular endothelial cells, it can be hypothesized that Fra2 mediates a specific TGF-␤1-dependent, ECM-specific genetic program in the vasculature, which can eventually contribute to the development of fibrosis.…”

OX40L blockade protects against inflammation-driven fibrosis

“…This result is of particular importance because fibrosing alveolitis is the leading cause of death in SSc, and no efficient therapy is yet available to treat this devastating condition (14,27). Furthermore, Fra-2 transgenic mice receiving anti-OX40L antibody had reduced perivascular inflammatory infiltrates and were protected against the vessel remodeling leading to PAH, the most extreme vascular phenotype of SSc (15,16). The role of OX40L in PAH is also supported by the observations in OX40L transgenic mice, which spontaneously develop severe PAH associated with massive lymphocytic perivascular infiltration (28).…”

“…S5). (14), we aimed to assess the effects of the OX40L mAb in the Fra-2 mouse model, which exhibits these severe involvements (15,16). Fra-2 transgenic mice displayed an increased expression of OX40 and OX40L in the skin and in the lungs as compared with control mice (Fig.…”

Advances in pathogenesis and treatment of systemic sclerosis

“…Pulmonary hypertension (PAH ) develops in 1-2% of SSc cases per year from three years of disease duration; this risk persists with prevalence at approximately 5% at 5 years, 10% at 10 years and 15% at 15 years. 8 Recent animal model studies 9,10 have better defined the potential mechanisms for the association in PAH, revealing that SSc may represent a phenocopy of bone morphogenetic protein receptor type II (BMPRII) deficiency that reflects transforming growth factor beta induced promotion of BMPRII protein degradation.…”