Potential for inhibition of checkpoint kinases 1/2 in pulmonary fibrosis and secondary pulmonary hypertension

Abstract

BackgroundIdiopathic pulmonary fibrosis (IPF) is a chronic lung disease characterised by exuberant tissue remodelling and associated with high unmet medical needs. Outcomes are even worse when IPF results in secondary pulmonary hypertension (PH). Importantly, exaggerated resistance to cell death, excessive proliferation and enhanced synthetic capacity are key endophenotypes of both fibroblasts and pulmonary artery smooth muscle cells, suggesting shared molecular pathways. Under persistent injury, sustained activation of the DNA damage response (DDR) is integral to the preservation of cells survival and their capacity to proliferate. Checkpoint kinases 1 and 2 (CHK1/2) are key components of the DDR. The objective of this study was to assess the role of CHK1/2 in the development and progression of IPF and IPF+PH.Methods and resultsIncreased expression of DNA damage markers and CHK1/2 were observed in lungs, remodelled pulmonary arteries and isolated fibroblasts from IPF patients and animal models. Blockade of CHK1/2 expression or activity-induced DNA damage overload and reverted the apoptosis-resistant and fibroproliferative phenotype of disease cells. Moreover, inhibition of CHK1/2 was sufficient to interfere with transforming growth factor beta 1-mediated fibroblast activation. Importantly, pharmacological inhibition of CHK1/2 using LY2606368 attenuated fibrosis and pulmonary vascular remodelling leading to improvement in respiratory mechanics and haemodynamic parameters in two animal models mimicking IPF and IPF+PH.ConclusionThis study identifies CHK1/2 as key regulators of lung fibrosis and provides a proof of principle for CHK1/2 inhibition as a potential novel therapeutic option for IPF and IPF+PH.

The Latest in Animal Models of Pulmonary Hypertension and Right Ventricular Failure

“…153 In this relatively easy-to-handle animal model with many variations in terms of dosage and route of delivery, muscularization of pulmonary vessels accompanied with or without the presence of mild PH has been repeatedly described. [154][155][156][157] Since elevation of RVSP in bleomycin-challenged rodents is most often modest and occurs concomitantly with the appearance of fibrotic lesions, a 2-hit rat model by sequential exposure to bleomycin and MCT was recently developed to more adequately recapitulate group 3 PH. 156,157 As revealed by histological analyses, hydroxyproline assay, lung function testing, and right heart catheterization, the combination of these insults results in pronounced fibrosis associated with altered mechanical properties of the respiratory system and a robust PH phenotype, 156,157 making this model more appropriate to assess the impact of drugs on the development of PH in preexisting pulmonary fibrosis.…”

AZD6738 Inhibits fibrotic response of conjunctival fibroblasts by regulating checkpoint kinase 1/P53 and PI3K/AKT pathways

“…CHK1 plays a key role in lung fibrosis ( Wu et al, 2022 ). The TGF-β1-treated HConFs, a model for inducing cellular fibrosis in vitro as mentioned above, were used to investigate the antifibrotic effects of AZD6738 in HConFs.…”

“…In recent years, CHK1, a major substrate of ATR as mentioned above, is proved to involve in the accumulation of activated myofibroblasts and secrete elevated levels of growth factors that stimulate cell proliferation and ECM production in both autocrine and paracrine manners, which underscores the pivotal role of CHK1 in myofibroblast activation ( Wu et al, 2022 ). However, the mechanism by altered ATR / CHK1 expression affects the activation of myofibroblasts and the synthesis of ECM protein is still unclear.…”

“…Cell cycle arrest in the G1 phase is mediated by P53, which is a substrate of CHK1 and ATR ( Feijoo et al, 2001 ; Heffernan et al, 2002 ). Recent research showed that CHK1 is a key regulator of lung fibrosis and CHK1 inhibition is considered as a potential novel therapeutic option for idiopathic pulmonary fibrosis ( Wu et al, 2022 ). Based on the clue, we hypothesized that CHK1 inhibitors have a potential role in subconjunctival fibrosis after trabeculectomy.…”

Targeted delivery of ZNF416 siRNA-loaded liposomes attenuates experimental pulmonary fibrosis

“…Pulmonary fibrosis is an advanced interstitial lung disease characterized by excessive ECM deposition with poor prognosis [ 15 , 16 ], including silicosis and IPF. Despite the current approved two antifibrotic medicine (nintedanib and pirfenidone) having been shown to reduce lung function decline, there is not enough to postpone fibrosis [ 17 ]. Recent results indicate that ZNF416 is a novel transcriptional regulator of fibroblast mechanoactivation [ 12 ], suggesting that this gene might be involved in matrix stiffness-induced fibrosis.…”