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-?-dependent pathways. Existing therapies only modestly slow the progression and likely only indirectly impact TGF-?-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-?, 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-??)n which leads to PF. This hypothesis is based on several lines of evidence: 1) TGF-? accumulates in lung tissues of PF, including IPF. 2) TGF-? inhibits normal lymphangiogenesis in lung tissues. 3) TGF-? induces lung edema by increasing epithelial and endothelial permeability. and 4) TGF-? is a major cytokine which is responsible for production of fibrotic extracellular matrix. This hypothesis suggests that, to ameliorate PF, TGF-? 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-? binding proteins (anti-TGF-? antibodies and soluble type II TGF-? receptors) and small-molecule inhibitors, which target latent-TGF-? activation and TGF-? 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-? receptor antagonist with both TGF-?-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.
Public Health Relevance Statement: Public Health Relevance: The goal of this project is to develop a novel TGF-? receptor antagonist, which exhibits anti-fibrotic and wound healing activities, as a drug candidate. It is expected to ameliorate and reverse lung fibrosis which currently lacks effective therapy. The clinical availability of this novel and potent antagonist will benefit millions of patients worldwie
NIH Spending Category: Lung
Project Terms: Address; Adult Respiratory Distress Syndrome; Affect; Alveolar; Amino Acids; Animal Model; Animals; Antibodies; Appearance; Area; Atherosclerosis; Attenuated; base; Binding; Binding Proteins; Biopsy; Bleomycin; Blood - brain barrier anatomy; Blood Circulation; Breathing; Cells; Cessation of life; Clinical; Collagen; Complex; cytokine; Defect; Deposition; Development; Diagnosis; Disease; Drainage procedure; drug candidate; Edema; effective therapy; Engineering; Epithelial; Exhibits; Extracellular Matrix; Extracellular Matrix Proteins; Failure; FDA approved; Fibroblasts; Fibronectins; Fibrosis; Fluorescein-5-isothiocyanate; Future; Glutamates; Goals; Half-Life; Hamman-Rich syndrome; Human; Hyaluronic Acid; in vivo; indium-bleomycin; Injury; insight; Insulin-Like Growth Factor Binding Protein 3; Lead; Lesion; Liquid substance; Lung; Lung diseases; lung injury; Lung Transplantation; Lymph; Lymphangiogenesis; Lymphatic; Lymphatic System; Lymphatic vessel; Mediating; Mediator of activation protein; Microscopic; Molecular; mortality; mouse model; Mus; novel; Pathogenesis; Pathway interactions; Patients; Penetration; Peptides; Permeability; Phosphotransferases; Plasma; Process; Production; Property; public health relevance; Pulmonary Edema; Pulmonary Fibrosis; Recycling; Respiratory physiology; response; Role; Route; Signal Transduction; small molecule inhibitor; Smooth Muscle Actin Staining Method; Structure; Structure of parenchyma of lung; Systemic Therapy; targeted agent; Therapeutic; therapeutic target; Time; Tissues; Transforming Growth Factor beta; Transforming Growth Factor beta Receptors; Vascular remodeling; Weight; Wound Healing
