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Pulmonary fibrosis (PF) occurs in various end stages of lung disease, and it is characterized by persistent scarring of the lung parenchyma with excessive deposition of extracellular matrix (ECM), leading to degressive quality of life and earlier mortality. FOXO4-D-Retro-Inverso (FOXO4-DRI), a synthesis peptide as a specific FOXO4 blocker, selectively induced dissociation of the FOXO4-p53 complex and nuclear exclusion of p53. Simultaneously, the p53 signaling pathway has been reported to activate in fibroblasts isolated from IPF fibrotic lung tissues and the p53 mutants cooperate with other factors that have the ability to disturb the synthesis of ECM. Yet, whether FOXO4-DRI influences the nuclear exclusion of p53 and then obstructs PF progress is still unknown. In this research, we explored the effect of FOXO4-DRI on bleomycin (BLM)-induced PF mouse model and activated fibroblasts model. The animal group of FOXO4-DRI therapeutic administration shows a milder pathologic change and less collagen deposition compared with the BLM-induced group. We also found the FOXO4-DRI resets the distribution of intranuclear p53 and concurrently decreased the total ECM proteins content. After further validation, FOXO4-DRI may well be a promising therapeutic approach to treating pulmonary fibrosis., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Idiopathic pulmonary fibrosis (IPF) is a fibrotic lung disease with poor prognosis. Epithelial-mesenchymal transition (EMT) has been reported to play an important role in IPF. The extracellular signal-regulated kinases 1 and 2 (ERK1/2) cascade, which regulates EMT and oncogenesis, has been implicated in the pathogenesis of IPF. Calpains, Ca 2+ -dependent cysteine proteinases that mediate controlled proteolysis of many specific substrates including epithelial cell marker E-cadherin, participate in organ fibrosis. Calpain-1 and calpain-2 of calpain family are ubiquitous calpains. ERK1/2 signaling stimulates the ubiquitous calpains activity in cancer development, but whether ERK1/2 signaling mediates the ubiquitous calpains activity in pulmonary fibrosis is unknown. Here we investigated whether inhibition of ERK1/2 signaling and the ubiquitous calpains attenuated experimental pulmonary fibrosis and examined the potential mechanism. Our results showed that inhibition of ERK1/2 signaling and the ubiquitous calpains both attenuated bleomycin (BLM)-induced lung fibrosis in mice. Inhibition of ERK1/2 signaling downregulated the expression of calpain-1 and calpain-2 in vivo and in vitro. We detected decreased E-cadherin expression and increased calpain-1 expression in IPF patients. Inhibition of ERK1/2 signaling and the ubiquitous calpains both suppressed the development of EMT in vivo and in vitro. Our study indicated that inhibition of the ERK1/2-ubiquitous calpains pathway protected pulmonary fibrosis from BLM, possibly via inhibition of EMT. Therefore, targeting ubiquitous calpains may be a potential strategy to attenuate IPF., Competing Interests: Declaration of competing interest No conflicts of interest, financial or otherwise, are declared by the author(s)., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

C/EBP homologous protein (Chop) has been shown to have altered expression in patients with idiopathic pulmonary fibrosis (IPF), but its exact role in IPF pathoaetiology has not been fully addressed. Studies conducted in patients with IPF and Chop(-/-) mice have dissected the role of Chop and endoplasmic reticulum (ER) stress in pulmonary fibrosis pathogenesis. The effect of Chop deficiency on macrophage polarization and related signalling pathways were investigated to identify the underlying mechanisms. Patients with IPF and mice with bleomycin (BLM)-induced pulmonary fibrosis were affected by the altered Chop expression and ER stress. In particular, Chop deficiency protected mice against BLM-induced lung injury and fibrosis. Loss of Chop significantly attenuated transforming growth factor β (TGF-β) production and reduced M2 macrophage infiltration in the lung following BLM induction. Mechanistic studies showed that Chop deficiency repressed the M2 program in macrophages, which then attenuated TGF-β secretion. Specifically, loss of Chop promoted the expression of suppressors of cytokine signaling 1 and suppressors of cytokine signaling 3, and through which Chop deficiency repressed signal transducer and activator of transcription 6/peroxisome proliferator-activated receptor gamma signaling, the essential pathway for the M2 program in macrophages. Together, our data support the idea that Chop and ER stress are implicated in IPF pathoaetiology, involving at least the induction and differentiation of M2 macrophages.

Interstitial lung disease (ILD) is a frequent extra-articular manifestation of rheumatoid arthritis (RA) and increases mortality in patients with RA. Early identification of ILD, especially the usual interstitial pneumonia (UIP) pattern with a poor prognosis, is important for guiding treatment of RA-ILD and preventing damage resulting from a delay in diagnosis. Interleukin-36 (IL-36) cytokines are involved in connective tissue diseases. However, IL-36 expression in RA-ILD is unknown. In this study, the clinical relevance of plasma IL-36 cytokines was evaluated in 39 patients with RA-ILD and three other groups (30 healthy controls [HCs], 35 RA patients without ILD, and 27 patients with idiopathic pulmonary fibrosis [IPF]) in the Chinese population. Plasma IL-36α and IL-36γ concentrations were elevated in patients with RA-ILD compared with those in HCs and patients with RA. RA-ILD patients with UIP pattern had higher plasma IL-36γ concentrations than those with RA-ILD without UIP, but these were lower than those in patients with IPF. Receiver operating curve analysis suggested that IL-36α and IL-36γ were potential biomarkers for identifying ILD in patients with RA. Additionally, the optimal cutoff value of IL-36γ for distinguishing RA-ILD with the UIP pattern from RA-ILD without UIP was 555.40 pg/mL and that for distinguishing RA-ILD from IPF was 655.10 pg/mL. No significant difference in plasma IL-36β or IL-36Ra concentrations was found between patients with RA-ILD and the three other groups. We also found that the lungs originating from different types of patients with PF, including RA-ILD and IPF, and those from mice following bleomycin-induced PF were characterized by increased IL-36γ expression. Our findings suggest that using IL-36 cytokines to identify patients with RA for further ILD workups may provide additional diagnostic value to the current clinically available assays. Moreover, IL-36γ may help to identify the presence of the UIP pattern in patients with RA-ILD and to discriminate RA-ILD from IPF. [ABSTRACT FROM AUTHOR]

Tissue remodeling/fibrosis is a main feature of idiopathic pulmonary fibrosis (IPF), which results in the replacement of normal lung parenchyma with a collagen-rich extracellular matrix produced by fibroblasts and myofibroblasts. Epithelial-mesenchymal transition (EMT) in type 2 lung epithelial cells is a key process in IPF, which leads to fibroblasts and myofibroblasts accumulation and excessive collagen deposition. DEC1, a structurally distinct class of basic helix-loop-helix proteins, is associated with EMT in cancer. However, the functional role of DEC1 in pulmonary fibrosis (PF) remains elusive. Herein, we aimed to explore DEC1 expression in IPF and bleomycin (BLM)-induced PF in mice and the mechanisms underlying the fibrogenic effect of DEC1 in PF in vivo and in vitro by Dec1 -knockout (Dec1 −/−) mice, knockdown and overexpression of DEC1 in alveolar epithelial cells (A549 cells). We found that the expression of DEC1 was increased in IPF and BLM-injured mice. More importantly, Dec1 −/− mice had reduced PF after BLM challenge. Additionally, DEC1 deficiency relieved EMT development and repressed the PI3K/AKT/GSK-3β/β-catenin integrated signaling pathway in mice and in A549 cells, whereas DEC1 overexpression in vitro had converse effects. Moreover, the PI3K/AKT and Wnt/β-catenin signaling inhibitors, LY294002 and XAV-939, ameliorated BLM-meditated PF in vivo and relieved EMT in vivo and in vitro. These pathways are interconnected by the GSK-3β phosphorylation status. Our findings indicated that during PF progression, DEC1 played a key role in EMT via the PI3K/AKT/GSK-3β/β-catenin integrated signaling pathway. Consequently, targeting DEC1 may be a potential novel therapeutic approach for IPF. [ABSTRACT FROM AUTHOR]

Despite past extensive studies, the mechanisms underlying pulmonary fibrosis (PF) still remain poorly understood. The aberrantly activated lung myofibroblasts, predominantly emerging through fibroblast-to-myofibroblast differentiation, are considered to be the key cells in PF, resulting in excessive accumulation of extracellular matrix (ECM). Latent transforming growth factor-β (TGFβ) binding protein-2 (LTBP2) has been suggested as playing a critical role in modulating the structural integrity of the ECM. However, its function in PF remains unclear. Here, we demonstrated that lungs originating from different types of patients with PF, including idiopathic PF and rheumatoid arthritis-associated interstitial lung disease, and from mice following bleomycin (BLM)-induced PF were characterized by increased LTBP2 expression in activated lung fibroblasts/myofibroblasts. Moreover, serum LTBP2 was also elevated in patients with COVID-19-related PF. LTBP2 silencing by lentiviral shRNA transfection protected against BLM-induced PF and suppressed fibroblast-to-myofibroblast differentiation in vivo and in vitro. More importantly, LTBP2 overexpression was able to induce differentiation of lung fibroblasts to myofibroblasts in vitro , even in the absence of TGFβ1. By further mechanistic analysis, we demonstrated that LTBP2 silencing prevented fibroblast-to-myofibroblast differentiation and subsequent PF by suppressing the phosphorylation and nuclear translocation of NF-κB signaling. LTBP2 overexpression-induced fibroblast-to-myofibroblast differentiation depended on the activation of NF-κB signaling in vitro. Therefore, our data indicate that intervention to silence LTBP2 may represent a promising therapy for PF. [ABSTRACT FROM AUTHOR]