New therapeutics based on emerging concepts in pulmonary fibrosis

Abstract

Introduction: 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 matri 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.

Lipid Mediators Regulate Pulmonary Fibrosis: Potential Mechanisms and Signaling Pathways

“…This review will specifically highlight the involvement of lipid mediators in pulmonary fibrosis (PF) and provide some mechanistic insights into the regulation of idiopathic pulmonary fibrosis (IPF) pathology by various lipid metabolites in animal models that mimic IPF. IPF is a progressive fibrotic disease of the lung of unknown etiology that occurs in older adults, diagnosed as usual interstitial pneumonia with a clinicopathologic criteria [7], wherein the lung tissue becomes thickened from scarring [8][9][10]. The compromised architecture leads to disturbed gas exchange, decreased lung compliance, and respiratory failure and death [11].…”

“…This review is specifically focused on the role of lipid-derived mediators and their signaling pathways modulating pulmonary fibrosis, in humans, and preclinical models. It is beyond the scope of this review to touch on all aspects of the disease since several recent reviews do justice in this context and will also sway the subject away from lipid signaling [9,10,12].…”

“…IPF is a progressive fibrotic disease of the lung of unknown etiology that occurs in older adults, diagnosed as usual interstitial pneumonia with a clinicopathologic criteria [ 7 ], wherein the lung tissue becomes thickened from scarring [ 8 , 9 , 10 ]. The compromised architecture leads to disturbed gas exchange, decreased lung compliance, and respiratory failure and death [ 11 ].…”

The Role of the Multidisciplinary Evaluation of Interstitial Lung Diseases: Systematic Literature Review of the Current Evidence and Future Perspectives

“…MDD is currently replacing the histological evaluation, due to its limited reliability and intrinsic risks particularly in elderly or highly comorbid patients (3). Given the poor prognosis of IPF and the availability of new anti-fibrotic drugs such as pirfenidone and nintedanib, the diagnosis formulated via MDD is currently considered the gold standard (4–6). Despite this guideline for IPF diagnosis, there are no available studies that clearly assess the impact of multidisciplinary team (MDT) in the approach to patients with ILD and we do not know if the evaluation by experts can actually be better than MDD.…”

Dysregulation of Mesenchymal Cell Survival Pathways in Severe Fibrotic Lung Disease: The Effect of Nintedanib Therapy

“…Fibrocytes are bone marrow-derived mesenchymal cells that express the hematopoietic cell-surface marker CD45 and mesenchymal cell-specific markers, such as collagens and vimentin (Pilling et al, 2009; Maharaj et al, 2013; Sontake et al, 2019). During injury and fibrosis, fibrocytes accumulate in distinct pathological areas of the lung (Madala et al, 2014b).…”