Idiopathic pulmonary fibrosis (IPF) is an ultimately fatal disease, characterized by progressive scar tissue formation leading to respiratory failure. There is a strong association between aging and IPF, however few studies have investigated the effects of aging on susceptibility to persistent lung fibrosis. Our preliminary studies indicate that aged mice exhibit persistent fibrosis in response to lung injury. We previously reported a critical role for NOX4/H2O2 in mediating myofibroblast functions and lung fibrosis. However, age-associated alterations in NOX4 expression as well as the role of NOX4/H2O2 in mediating pro-fibrotic lung myofibroblast phenotypes (senescence, apoptosis-resistance) have not previously been reported. The proposed studies, we will explore the hypothesis that, in the context of aging, NOX4 contributes to persistent fibrosis by the accumulation of senescent myofibroblasts, which may then induce apoptosis of epithelial cells. We propose to develop a novel animal model of persistent fibrosis in aged mice, which more accurately mimics the persistent/progressive fibrosis seen in IPF patients. These studies will provide: (1) more relevant ex vivo and in vivo experimental models for investigation of IPF and pre-clinical evaluation;(2) novel insights into the role of aging andin the pathogenesis of IPF;and, (3) expanded roles of NOX4/H2O2 in aging and further proof-of-concept for therapeutic targeting NOX4 in fibrotic diseases.
Even in the absence of disease, aging is accompanied by changes in pulmonary physiology. These age-related changes may increase susceptibility to pulmonary disease. Idiopathic pulmonary fibrosis (IPF) is characterized by progressive scar tissue formation leading to respiratory failure, which is prevalent in the elderly population. Understanding lung injury-repair in the context of aging may offer novel insights for the development of therapeutic interventions aimed to treat fibrotic diseases, such as IPF.
|Hecker, Louise (2018) Mechanisms and consequences of oxidative stress in lung disease: therapeutic implications for an aging populace. Am J Physiol Lung Cell Mol Physiol 314:L642-L653|
|Chanda, Diptiman; Kurundkar, Ashish; Rangarajan, Sunad et al. (2016) Developmental Reprogramming in Mesenchymal Stromal Cells of Human Subjects with Idiopathic Pulmonary Fibrosis. Sci Rep 6:37445|
|Hecker, Louise; Thannickal, Victor J (2016) Getting to the core of fibrosis: targeting redox imbalance in aging. Ann Transl Med 4:93|
|Qian, Zhongqing; Zhou, Tong; Gurguis, Christopher I et al. (2015) Nuclear factor, erythroid 2-like 2-associated molecular signature predicts lung cancer survival. Sci Rep 5:16889|
|Hecker, Louise; Logsdon, Naomi J; Kurundkar, Deepali et al. (2014) Reversal of persistent fibrosis in aging by targeting Nox4-Nrf2 redox imbalance. Sci Transl Med 6:231ra47|
|Bernard, Karen; Hecker, Louise; Luckhardt, Tracy R et al. (2014) NADPH oxidases in lung health and disease. Antioxid Redox Signal 20:2838-53|