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 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
• idiopathic pulmonary fibrosis
• lung
• myofibroblasts
• Wilms’ tumor1

Article highlights

• Lung resident fibroblasts contribute to the major pool of myofibroblast in fibrotic lung lesions.

• Fibrocytes secrete paracrine factors and induce lung resident fibroblast activation.

• Transcription factors such as FoxF1, FoxM1 and WT1 play an important role in fibroproliferation and myofibroblast transformation.

• Hsp90 is a positive regulator of fibroblast activation and inhibition of Hsp90 ATPase activity attenuates pulmonary fibrosis.

• TGFβ1 is a major fibrogenic factor and improvement in strategies to inhibit TGFβ1-driven signaling may help to combat with fibrosis.

• Infiltration of immune cells and excessive Th2 cytokine production contributes to pulmonary fibrosis.

• Inhibition of multiple signaling pathways that are heightened in IPF lungs such as RhoA, ROCK, MAPK, PI3K, AKT, and mTOR pathways may offer a therapeutic advantage with unclear mechanism of action.

• Elucidating the underlying mechanisms of the ECM clearance and the regenerative capacity in lungs are of interest to improve fibrosis resolution.

• Combinatorial therapeutic strategies are urgently needed that not only delay the progression but also reverse established and ongoing fibrosis in lungs.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

This paper was not funded. This work was supported by grants from the National Institutes of Health [1R01 HL134801 and 1R21AG059533] and the Department of Defence grant [W81XWH-17-1-0666] for SK Madala and a Cystic Fibrosis Foundation Fellowship for V Sontake