A Novel TGF-β Receptor Antagonist to Treat Pulmonary Fibrosis

 描述(申请人提供)：肺纤维化(PF)，包括特发性肺纤维化(IPF)，是一组进展性不可治愈的肺部疾病，死亡率高。肺纤维化的特征是通过转化生长因子-β依赖的途径在肺实质过度沉积细胞外基质蛋白。现有的治疗方法只是略微减缓了进展，而且可能只间接影响转化生长因子-β介导的通路。最近发现的异常淋巴管生成参与了IPF和博莱霉素诱导的PF，这为可能限制系统治疗的细胞和分子机制提供了新的见解。据推测，肺损伤后发生的血管重塑会导致透明质酸沉积，透明质酸是淋巴的一种成分，也是一种微弱的淋巴管生成因子。这会导致淋巴管生成异常，从而产生具有功能缺陷(淋巴引流缺陷)的新淋巴管，导致反复损伤和纤维化的恶性循环。淋巴管生成异常是PF的一个限速步骤，为未来吸入PF治疗提供了一个很好的靶点。淋巴管生成异常在PF形成中的作用的分子基础尚不清楚。我们推测，转化生长因子-β是肺损伤后产生的一种强有力的促纤维化细胞因子，参与了肺损伤后血管重塑过程中淋巴管的异常生成，并参与了反复损伤和纤维化的恶性循环(损伤、异常淋巴管生成、淋巴引流缺陷和转化生长因子-→)的积聚，从而导致肺功能衰竭。这一假说基于以下几条证据：1)转化生长因子-β在肺间质纤维化，包括肺间质纤维化的肺组织中积聚。2)转化生长因子-β抑制肺组织正常淋巴管生成。3)转化生长因子-β通过增加内皮细胞和上皮细胞的通透性而导致肺水肿。(4)转化生长因子-β是肝纤维化细胞外基质产生的主要细胞因子。这一假说提示，肺内给药靶向肺引流淋巴系统的转化生长因子-β拮抗剂改善肺功能，不仅可以抑制基质的产生，而且可以抑制反复损伤和纤维化的循环。在过去的十年中，针对潜在的转化生长因子-β激活和转化生长因子-β信号转导的转化生长因子-β结合蛋白(抗转化生长因子-β抗体和可溶性II型转化生长因子-β受体)和小分子抑制剂已经被开发出来并用于动物模型的治疗。然而，肺引流淋巴管并不是这些治疗的具体目标。这将限制它们在治疗人类患者方面的有效性。此外，这些药物具有全身性和非靶向性效应，导致治疗窗口狭窄。为了解决有限的疗效和非靶点效应，我们开发了一种新型的转化生长因子-β受体拮抗剂，既具有转化生长因子-β拮抗剂活性，又具有促进伤口愈合的活性。它可以有效、安全和负担得起地用于人类PF的管理。在这个项目中，我们将确定这种拮抗剂通过鼻腔给药治疗PF的疗效，该药物的靶点是 两种肺纤维化小鼠模型的肺淋巴系统和肺实质。我们期望这些拟议研究的结果将导致一种新的有效的PF治疗方法。

 DESCRIPTION (provided by applicant): Pulmonary fibrosis (PF), including idiopathic PF (IPF), is a group of progressive incurable lung diseases with high mortality rates. PF is characterized by excessive deposition of extracellular matrix proteins in lung parenchyma via TGF-β-dependent pathways. Existing therapies only modestly slow the progression and likely only indirectly impact TGF-β-mediated pathways. Recent identification of the involvement of abnormal lymphangiogenesis in IPF and bleomycin-induced PF has provided new insights into cellular and molecular mechanisms that may limit systemic therapeutics. It is hypothesized that vascular remodeling, which occurs after lung injury, leads to deposition of hyaluronic acid, a component of lymph and a weak lymphangiogenesis factor. This results in abnormal lymphangiogenesis which produces new lymphatic vessels with functional defects (lymphatic drainage defects), leading to the vicious cycle of repeated injury and fibrosis. Abnormal lymphangiogenesis, a rate-limiting step in PF, offers an excellent target for future inhaled PF therapeutics. The molecular basis of the role of abnormal lymphangiogenesis in the formation of PF is unknown. We hypothesize that TGF-β, a potent fibrogenic cytokine produced in lung upon injury, contributes to abnormal lymphangiogenesis which occurs during vascular remodeling after lung injury, and is involved in the vicious cycle of repeated injury and fibrosis (injury→ abnormal lymphangiogenesis→ lymphatic drainage defects→ accumulation of TGF-β→)n which leads to PF. This hypothesis is based on several lines of evidence: 1) TGF-β accumulates in lung tissues of PF, including IPF. 2) TGF-β inhibits normal lymphangiogenesis in lung tissues. 3) TGF-β induces lung edema by increasing epithelial and endothelial permeability. and 4) TGF-β is a major cytokine which is responsible for production of fibrotic extracellular matrix. This hypothesis suggests that, to ameliorate PF, TGF-β antagonists targeted to the lung draining lymphatic systems by intrapulmonary administration can inhibit not only the matrix production but the cycle of repeated injury and fibrosis. In the last decade, TGF-β binding proteins (anti-TGF-β antibodies and soluble type II TGF-β receptors) and small-molecule inhibitors, which target latent-TGF-β activation and TGF-β signaling, have been developed and used to treat PF in animal models. However, the lung draining lymphatics are not specifically targeted in these treatments. This will limit their efficacy in treating human patients. In additio, these agents have systemic and off-target effects that result in narrow therapeutic windows. To address the limited efficacy and off-target effects, we generated a novel TGF-β receptor antagonist with both TGF-β-antagonist and wound healing-promoting activities. It can be effectively, safely and affordably used for the management of PF in humans. In this project, we will determine the efficacy of this antagonist in treating PF by intranasal delivery, which targets the lung lymphatic system and lung parenchyma, in two mouse models of lung fibrotic disease. We expect that the results from these proposed studies will lead to a novel effective therapy of PF in patients.