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Caveolin-1 peptide regulates p53-microRNA-34a feedback in fibrotic lung fibroblasts.

ABSTRACT: Idiopathic pulmonary fibrosis (IPF) is a life-threatening disease resulting from dysregulated repair responses to lung injury. Excessive extracellular matrix deposition by expanding myofibroblasts and fibrotic lung fibroblasts (fLfs) has been implicated in the pathogenesis of PF, including IPF. We explored fLfs' microRNA-34a (miR-34a) expression from IPF tissues. Basal miR-34a levels were decreased with reduced binding of p53 to the promoter DNA and 3'UTR mRNA sequences. Overexpression of miR-34a in fLfs increased p53, PAI-1, and reduced pro-fibrogenic markers. The regulatory effects of miR-34a were altered by modifying the p53 expression. Precursor-miR-34a lung transduction reduced bleomycin-induced PF in wild-type mice. fLfs treated with caveolin-1 scaffolding domain peptide (CSP) or its fragment, CSP7, restored miR-34a, p53, and PAI-1. CSP/CSP7 reduced PDGFR-β and pro-fibrogenic markers, which was abolished in fLfs following blockade of miR-34a expression. These peptides failed to resolve PF in mice lacking miR-34a in fLfs, indicating miR-34a-p53-feedback induction required for anti-fibrotic effects.

SUBMITTER: Hogan TB

PROVIDER: S-EPMC8938287 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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Caveolin-1 peptide regulates p53-microRNA-34a feedback in fibrotic lung fibroblasts.

Hogan Taryn B TB Tiwari Nivedita N Nagaraja M R MR Shetty Shwetha K SK Fan Liang L Shetty Rashmi S RS Bhandary Yashodhar P YP Shetty Sreerama S

iScience 20220303 4

Idiopathic pulmonary fibrosis (IPF) is a life-threatening disease resulting from dysregulated repair responses to lung injury. Excessive extracellular matrix deposition by expanding myofibroblasts and fibrotic lung fibroblasts (fLfs) has been implicated in the pathogenesis of PF, including IPF. We explored fLfs' microRNA-34a (miR-34a) expression from IPF tissues. Basal miR-34a levels were decreased with reduced binding of p53 to the promoter DNA and 3'UTR mRNA sequences. Overexpression of miR-34 ...[more]

PMID: 35330685

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Project description:Reduced caveolin-1 levels in lung fibroblasts from patients with scleroderma and the lungs of bleomycin-treated mice promote collagen overexpression and lung fibrosis. This study was undertaken to determine whether caveolin-1 is deficient in leucocytes from bleomycin-treated mice and patients with scleroderma and to examine the consequences of this deficiency and its reversal.Mice or cells received the caveolin-1 scaffolding domain (CSD) peptide to reverse the pathological effects of reduced caveolin-1 expression. In bleomycin-treated mice, the levels of caveolin-1 in leucocytes and the effect of CSD peptide on leucocyte accumulation in lung tissue were examined. To validate the results in human disease and to identify caveolin-1-regulated molecular mechanisms, monocytes and neutrophils were isolated from patients with scleroderma and control subjects and caveolin-1, extracellular signal-regulated protein kinase (ERK), c-Jun N-terminal kinase (JNK), p38, CXC chemokine receptor 4 (CXCR4) and matrix metalloproteinase 9 (MMP-9) expression/activation were evaluated. These parameters were also studied in monocytes treated with cytokines or CSD peptide.Leucocyte caveolin-1 is important in lung fibrosis. In bleomycin-treated mice, caveolin-1 expression was diminished in monocytes and CSD peptide inhibited leucocyte recruitment into the lungs. These observations are relevant to human disease. Monocytes and neutrophils from patients with scleroderma contained less caveolin-1 and more activated ERK, JNK and p38 than those from control subjects. Treatment with CSD peptide reversed ERK, JNK and p38 hyperactivation. Scleroderma monocytes also overexpressed CXCR4 and MMP-9, which was inhibited by the CSD peptide. Cytokine treatment of normal monocytes caused adoption of the scleroderma phenotype (low caveolin-1, high CXCR4 and MMP-9 and signalling molecule hyperactivation).Caveolin-1 downregulation in leucocytes contributes to fibrotic lung disease, highlighting caveolin-1 as a promising therapeutic target in scleroderma.

Project description:Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease (ILD) for which there are no effective treatments. Lung transplantation is the only viable option for patients with end-stage PF but is only available to a minority of patients. Lung lesions in ILDs, including IPF, are characterized by alveolar epithelial cell (AEC) senescence and apoptosis and accumulation of activated myofibroblasts and/or fibrotic lung (fL) fibroblasts (fLfs). These composite populations of fLfs show a high rate of basal proliferation, resist apoptosis and senescence, and have increased migration and invasiveness. They also more readily deposit ECM proteins. These features eventuate in progressive destruction of alveolar architecture and loss of lung function in patients with PF. The identification of new, safer, and more effective therapy is therefore mandatory for patients with IPF or related ILDs. We found that increased caveolin-1 and tumor suppressor protein, p53 expression, and apoptosis in AECs occur prior to and then with the proliferation of fLfs in fibrotic lungs. AECs with elevated p53 typically undergo apoptosis. fLfs alternatively demonstrate strikingly low basal levels of caveolin-1 and p53, while mouse double minute 2 homolog (mdm2) levels and mdm2-mediated degradation of p53 protein are markedly increased. The disparities in the expression of p53 in injured AECs and fLfs appear to be due to increased basal expression of caveolin-1 in apoptotic AECs with a relative paucity of caveolin-1 and increased mdm2 in fLfs. Therefore, targeting caveolin-1 using a caveolin 1 scaffolding domain peptide, CSP7, represents a new and promising approach for patients with IPF, perhaps other forms of progressive ILD or even other forms of organ injury characterized by fibrotic repair. The mechanisms of action differ in the injured AECs and in fLfs, in which differential signaling enables the preservation of AEC viability with concurrent limitation of fLf expansion and collagen secretion. The findings in three models of PF indicate that lung scarring can be nearly abrogated by airway delivery of the peptide. Phase 1 clinical trial testing of this approach in healthy volunteers has been successfully completed; Phase 1b in IPF patients is soon to be initiated and, if successful, will be followed by phase 2 testing in short order. Apart from the treatment of IPF, this intervention may be applicable to other forms of tissue injury characterized by fibrotic repair.

Dataset Information

Caveolin-1 peptide regulates p53-microRNA-34a feedback in fibrotic lung fibroblasts.

Publications

Caveolin-1 peptide regulates p53-microRNA-34a feedback in fibrotic lung fibroblasts.

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