New therapeutics based on emerging concepts in pulmonary fibrosis

Abstract

Fibrosis is an irreversible pathological endpoint in many chronic diseases, including pulmonary fibrosis. Idiopathic pulmonary fibrosis (IPF) is a progressive and often fatal condition characterized by (myo)fibroblast proliferation and transformation in the lung, expansion of the extracellular matrix, and extensive remodeling of the lung parenchyma. Recent evidence indicates that IPF prevalence and mortality rates are growing in the United States and elsewhere. Despite decades of research on the pathogenic mechanisms of pulmonary fibrosis, few therapeutics have succeeded in the clinic, and they have failed to improve IPF patient survival. Areas covered: Based on a literature search and our own results, we discuss the key cellular and molecular responses that contribute to (myo)fibroblast actions and pulmonary fibrosis pathogenesis; this includes signaling pathways in various cells that aberrantly and persistently activate (myo)fibroblasts in fibrotic lesions and promote scar tissue formation in the lung. Expert opinion: Lessons learned from recent failures and successes with new therapeutics point toward approaches that can target multiple pro-fibrotic processes in IPF. Advances in preclinical modeling and single-cell genomics will also accelerate novel discoveries for effective treatment of IPF.

Keywords: Heat shock protein 90; Wilms’ tumor1; idiopathic pulmonary fibrosis; lung; myofibroblasts.

Figure 1:. Tissue fibrosis and associated diseases

Tissue fibrosis is a major cause of death worldwide due to organ failure as several chronic diseases are associated with severe fibrosis leading to organ failure due to impairment in the regulation of inflammation, metabolic pathways and infections. Monogenic mutations could lead to malformed proteins which can manifest into impaired tissue remodeling and fibrosis in chronic diseases such as Cystic Fibrosis (CF), Duchenne Muscular Dystrophy (DMD) and familial interstitial lung diseases (fILD).

Figure 2:. The cellular pathway of fibrocyte-driven (myo)fibrobalst activation in severe fibrotic lung disease.

Fibrocytes originate from monocyte progenitors and migrate to fibrotic lesions of injured lungs to secrete paracrine factors that can cause fibroproliferation and fibroblast-to-myofibroblast (FMT) transformation in the pathogenesis of pulmonary fibrosis.