JNK inhibition reduces lung remodeling and pulmonary fibrotic systemic markers

Abstract

BackgroundLung remodeling and pulmonary fibrosis are serious, life‐threatening conditions resulting from diseases such as chronic severe asthma and idiopathic pulmonary fibrosis (IPF). Preclinical evidence suggests that JNK enzyme function is required for key steps in the pulmonary fibrotic process. However, a selective JNK inhibitor has not been investigated in translational models of lung fibrosis with clinically relevant biomarkers, or in IPF patients. MethodsThe JNK inhibitor CC‐930 was evaluated in the house dust mite‐induced fibrotic airway mouse model, in a phase I healthy volunteer pharmacodynamic study, and subsequently in a phase II multicenter study of mild/moderate IPF (n = 28), with a 4‐week, placebo‐controlled, double‐blind, sequential ascending‐dose period (50 mg QD, 100 mg QD, 100 mg BID) and a 52‐week open‐label treatment‐extension period. ResultsIn the preclinical model, CC‐930 attenuated collagen 1A1 gene expression, peribronchiolar collagen deposition, airway mucin MUC5B expression in club cells, and MMP‐7 expression in lung, bronchoalveolar lavage fluid, and serum. In the phase I study, CC‐930 reduced c‐Jun phosphorylation induced by UV radiation in skin. In the phase II IPF study, there was a CC‐930 dose‐dependent trend in reduction of MMP‐7 and SP‐D plasma protein levels. The most commonly reported adverse events were increased ALT, increased AST, and upper respiratory tract infection (six subjects each, 21.4 %). A total of 13 subjects (46.4 %) experienced adverse events that led to discontinuation of study drug. Nine out of 28 subjects experienced progressive disease in this study. The mean FVC (% predicted) declined after 26–32 weeks at doses of 100 mg QD and 100 mg BID. Changes in MMP‐7, SP‐D, and tenascin‐C significantly correlated with change in FVC (% predicted). ConclusionsThese results illustrate JNK enzymatic activity involvement during pulmonary fibrosis, and support systemic biomarker use for tracking disease progression and the potential clinical benefit of this novel intervention in IPF. Trial registration ClinicalTrials.gov NCT01203943

c‐Jun N‐terminal kinase in pancreatic tumor stroma augments tumor development in mice

“…CC-930 is being tested in idiopathic pulmonary fibrosis and high-dose CC-930 caused elevation of hepatic transaminases when used for long-term treatment. (36) AS602801 is being tested in endometriosis and demonstrated favorable safety and tolerability after 5 months of administration. (37,38) Both diseases are benign, chronic inflammatory diseases, and the efficacy of the inhibitors has not been examined in malignant tumor patients; our results suggest that it is worth examining the safety and tolerability in those patients.…”

Increased expression of desmin and vimentin reduces bladder smooth muscle contractility via JNK2

“…45 The JNK inhibitor CC-930 attenuated lung remodeling and collagen deposition and other pulmonary fibrotic systemic markers in house dust mite-induced fibrotic airway mouse model. 46 JNK1 and JNK2 KO mice were protected against hypercholesterolemia-induced endothelial dysfunction and atheroma formation. [47][48][49] The contribution of JNK2 signaling to muscle remodeling is increasingly appreciated.…”

MicroRNAs orchestra the cellular processes driving failure of the heart

“…In particular, overexpression of miR-221 in normal rat kidney fibroblasts (NRK-49F cells) is able to prevent the angiotensin II-induced expression of fibronectin and alpha smooth muscle actin (αSMA) through targeting of ETS-1 [18]. Various reports have shown that the stress-activated protein kinase JNK1 is required for the development of fibrosis in multiple organs, including the liver [41,42], lung [43,44], kidney [45], and heart [46]. In particular, JNK1 is necessary for expression of profibrotic genes through stimulation of fibroblast activation, proliferation and transdifferentiation into myofibroblasts [45,[47][48][49].…”

“…Rapid dissociation of ribosomes in a miRNA-dependent manner represses elongation and prevents mRNA translation [41]. The current paradigm prevails that miRNAmRNA target interaction may lead to reductions in mRNA abundance due to an increase in mRNA degradation because of deadenylation, decapping, and exonucleolytic digestion of the mRNA [42,43]. In support of this model, many repressed mRNAs are deadenylated by miRNAs in vivo [42] and in vitro [40].…”

“…MiR-21, miR-132 and miR-222 are also directly involved in controlling calcium levels via targeting, beta-2 subunit of the voltage-dependent calcium channel (CACNB2) [42]. Moreover, Ling et al [43] have shown that miR-26b, miR-21, and miR-320 levels are affected by changes in βAR activity.…”