Yeungnam Univ J Med.  2020 Oct;37(4):269-276. 10.12701/yujm.2020.00458.

Therapeutic potential of targeting kinase inhibition in patients with idiopathic pulmonary fibrosis

• Kim S
• Lim JH
• Woo CH

• KMID: 2508171
• DOI: http://doi.org/10.12701/yujm.2020.00458

Abstract

Fibrosis is characterized by excessive accumulation of extracellular matrix components. The fibrotic process ultimately leads to organ dysfunction and failure in chronic inflammatory and metabolic diseases such as pulmonary fibrosis, advanced kidney disease, and liver cirrhosis. Idiopathic pulmonary fibrosis (IPF) is a common form of progressive and chronic interstitial lung disease of unknown etiology. Pathophysiologically, the parenchyma of the lung alveoli, interstitium, and capillary endothelium becomes scarred and stiff, which makes breathing difficult because the lungs have to work harder to transfer oxygen and carbon dioxide between the alveolar space and bloodstream. The transforming growth factor beta (TGF-) signaling pathway plays an important role in the pathogenesis of pulmonary fibrosis and scarring of the lung tissue. Recent clinical trials focused on the development of pharmacological agents that either directly or indirectly target kinases for the treatment of IPF. Therefore, to develop therapeutic targets for pulmonary fibrosis, it is essential to understand the key factors involved in the pathogenesis of pulmonary fibrosis and the underlying signaling pathway. The objective of this review is to discuss the role of kinase signaling cascades in the regulation of either TGF--dependent or other signaling pathways, including Rho-associated coiled-coil kinase, c-jun N-terminal kinase, extracellular signal-regulated kinase 5, and p90 ribosomal S6 kinase pathways, and potential therapeutic targets in IPF.

Keyword

Fibrosis; Idiopathic pulmonary fibrosis; Kinase; Transforming growth factor beta

Figure

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  Fig. 1. Roles of extracellular signal-regulated kinase 5 (ERK5) and p90 ribosomal S6 kinase (p90RSK) in pulmonary fibrosis. (A) ERK5 may be activated by multiple receptors involved in pulmonary fibrosis. (B) Transforming growth factor beta (TGF-β) activates ERK5 and p90RSK in lung alveolar epithelial cells and lung fibroblasts. Activation of ERK5 or p90RSK regulates Smad3 transcriptional activity via acetylation modification. The pharmacological inhibitors of ERK5 or p90RSK reduce TGF-β-induced fibrogenic gene expression and experimental lung fibrosis. TGFR, transforming growth factor receptor; FGFR, fibroblast growth factor receptor; PDGFR, platelet-derived growth factor receptor; EGFR, epidermal growth factor receptor; VEGFR, vascular endothelial growth factor receptor; P, phosphorylation; A, acetylation; HAT, histone acetyltransferase.

Reference

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