Cells. 2022 Jun 2;11(11):1820. doi: 10.3390/cells11111820.

ABSTRACT

In idiopathic pulmonary fibrosis (IPF), keratin (KRT)17+/KRT5+ basal and KRT17+/KRT5- aberrant basaloid cells are atypically present within the alveolar space. We previously described the fibrosis-enriched outgrowth of alveolar basal cells from peripheral fibrotic lung tissue. Using single cell RNA sequencing (scRNA-seq), we here characterize the transcriptome of these cultured alveolar basal cells under different culture conditions.

METHODS: Fibrotic peripheral lung tissue pieces were placed in DMEM growth medium. Outgrown cells were analysed by scRNA-seq, TaqMan-PCR or immunofluorescence (IF) either directly or after medium change to an epithelial cell specific medium (Cnt-PR-A).

RESULTS: A fraction of alveolar basal cells cultured in DMEM growth medium showed close transcriptomic similarities to IPF basal cells. However, although they expressed KRT5, the transcriptome of the majority of cells matched best to the transcriptome of recently described KRT17+/KRT5- aberrant basaloid cells, co-expressing the canonical basal cell marker KRT17 and mesenchymal cell marker (VIM, FN1). A smaller fraction of cells matched best to secretory epithelial cells. Two differentiation gradients from basal to aberrant basaloid-like cells and basal to secretory epithelial-like cells were apparent. Interestingly, these differentiation paths seemed reversed when the cell culture medium was changed to Cnt-PR-A.

CONCLUSIONS: Our results suggest that cultured alveolar basal cells have the capacity to differentiate towards secretory epithelial-like cells and to aberrant basaloid-like cells. However, due to the persistent expression of KRT5, a complete differentiation towards aberrant basaloid cells did not seem to be achieved in our culture conditions. Importantly, differentiation seemed reversible by changing the cells microenvironment. Determining specific factors influencing these differentiation paths may help to define novel drug targets for IPF therapy.

PMID:35681516 | DOI:10.3390/cells11111820

Cells. 2022 May 29;11(11):1781. doi: 10.3390/cells11111781.

ABSTRACT

Cellular senescence represents a state of irreversible cell cycle arrest occurring naturally or in response to exogenous stressors. Following the initial arrest, progressive phenotypic changes define conditions of cellular senescence. Understanding molecular mechanisms that drive senescence can help to recognize the importance of such pathways in lung health and disease. There is increasing interest in the role of cellular senescence in conditions such as chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) in the context of understanding pathophysiology and identification of novel therapies. Herein, we discuss the current knowledge of molecular mechanisms and mitochondrial dysfunction regulating different aspects of cellular senescence-related to chronic lung diseases to develop rational strategies for modulating the senescent cell phenotype in the lung for therapeutic benefit.

PMID:35681476 | DOI:10.3390/cells11111781

Chest. 2022 Jun;161(6):1440-1441. doi: 10.1016/j.chest.2022.02.018.

NO ABSTRACT

PMID:35680308 | DOI:10.1016/j.chest.2022.02.018

Respir Res. 2022 Jun 8;23(1):149. doi: 10.1186/s12931-022-02076-9.

ABSTRACT

BACKGROUND: Dehydroepiandrosterone (DHEA) is a precursor sex hormone with antifibrotic properties. The aims of this study were to investigate antifibrotic mechanisms of DHEA, and to determine the relationship between DHEA-sulfate (DHEAS) plasma levels, disease severity and survival in patients with fibrotic interstitial lung diseases (ILDs).

METHODS: Human precision cut lung slices (PCLS) and normal human lung fibroblasts were treated with DHEA and/or transforming growth factor (TGF)-β1 before analysis of pro-fibrotic genes and signal proteins. Cell proliferation, cytotoxicity, cell cycle and glucose-6-phosphate dehydrogenase (G6PD) activity were assessed. DHEAS plasma levels were correlated with pulmonary function, the composite physiologic index (CPI), and time to death or lung transplantation in a derivation cohort of 31 men with idiopathic pulmonary fibrosis (IPF) and in an independent validation cohort of 238 men and women with fibrotic ILDs.

RESULTS: DHEA decreased the expression of pro-fibrotic markers in-vitro and ex-vivo. There was no cytotoxic effect for the applied concentrations, but DHEA interfered in proliferation by modulating the cell cycle through reduction of G6PD activity. In men with IPF (derivation cohort) DHEAS plasma levels in the lowest quartile were associated with poor lung function and higher CPI (adjusted OR 1.15 [95% CI 1.03-1.38], p = 0.04), which was confirmed in the fibrotic ILD validation cohort (adjusted OR 1.03 [95% CI 1.00-1.06], p = 0.01). In both cohorts the risk of early mortality was higher in patients with low DHEAS levels, after accounting for potential confounding by age in men with IPF (HR 3.84, 95% CI 1.25-11.7, p = 0.02), and for age, sex, IPF diagnosis and prednisone treatment in men and women with fibrotic ILDs (HR 3.17, 95% CI 1.35-7.44, p = 0.008).

CONCLUSIONS: DHEA reduces lung fibrosis and cell proliferation by inducing cell cycle arrest and inhibition of G6PD activity. The association between low DHEAS levels and disease severity suggests a potential prognostic and therapeutic role of DHEAS in fibrotic ILD.

PMID:35676709 | DOI:10.1186/s12931-022-02076-9

Am J Respir Cell Mol Biol. 2022 Jun 8. doi: 10.1165/rcmb.2022-0107TR. Online ahead of print.

ABSTRACT

COVID19 begins with upper airway symptoms but proceeds in a significant proportion of patients to life-threatening infection of the lower respiratory tract, where an exuberant inflammatory response, edema, and adverse parenchymal remodeling impair gas exchange. Respiratory failure is caused initially by flooding of the airspaces with plasma exudate, sloughed epithelium, and inflammatory cells. For many patients with COVID19, this acute phase has been observed to give way to a prolonged course of acute respiratory distress syndrome (ARDS), and a significant proportion of patients go on to develop fibroproliferative remodeling of the lung parenchyma, which lengthens the duration of respiratory impairment and mechanical ventilation. Monocyte-derived macrophages have previously been implicated in the fibrotic phase of lung injury in multiple models. From several recent studies that employed single cell genomic techniques, a profile of the transcriptomic state of COVID19 lung macrophages has emerged. Linkages have been made between these macrophages, which are monocyte-derived and CD163+, and profibrotic macrophages found in other contexts, including animal models of fibrosis and Idiopathic Pulmonary Fibrosis. Here, emerging concepts of macrophage profibrotic function in COVID19 are highlighted, with a focus on gaps in knowledge to be addressed by future research. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

PMID:35675555 | DOI:10.1165/rcmb.2022-0107TR

N Engl J Med. 2022 Jun 9;386(23):2235-2236. doi: 10.1056/NEJMe2205411.

NO ABSTRACT

PMID:35675182 | DOI:10.1056/NEJMe2205411

Expert Rev Respir Med. 2022 Jun 8:1-10. doi: 10.1080/17476348.2022.2085091. Online ahead of print.

ABSTRACT

INTRODUCTION: Pulmonary fibrosis is an age-related, progressive, and fatal disease with a median survival of 3-5 years after diagnosis; idiopathic pulmonary fibrosis (IPF) is the most common type. It is characterized by fibroblast proliferation and accumulation of excessive extracellular matrix. Patients with IPF are at increased risk for lung cancer. Epigenetic mechanisms are involved in lung fibrosis and cancer, and DNA methylation is critical in disease pathogenesis and progression. Therefore, studies of DNA methylation contribute to better understanding of the underlying mechanisms of these two respiratory diseases, and can offer novel diagnostic and treatment options.

AREAS COVERED: This review discusses the latest advances in our understanding of epigenetic factors related to DNA methylation that impact development of lung cancer and pulmonary fibrosis, discusses the role of DNA methylation in promoting or inhibiting these diseases, and proposes its potential clinical significance in disease diagnosis and treatment.

EXPERT OPINION: DNA methylation plays a critical role in lung cancer and fibrosis pathogenesis. DNA methylation offers a new biomarker for disease diagnosis or monitoring, and provides a new therapeutic target for treatment.

PMID:35673969 | DOI:10.1080/17476348.2022.2085091

BMC Complement Med Ther. 2022 Jun 7;22(1):151. doi: 10.1186/s12906-022-03637-7.

ABSTRACT

BACKGROUNDS: Asthma and idiopathic pulmonary fibrosis (IPF) are common chronic diseases of the respiratory system in clinical practice. However, the relationship and molecular links remain unclear, and the current treatment's efficacy is disappointing. Bu-Shen-Yi-Qi (BSYQ) decoction has proven effective in treating various chronic airway inflammatory diseases, including asthma and IPF. But the underlying pharmacological mechanisms are still to be elucidated.

METHODS: This study searched the proteins related to asthma and IPF via TTD, CTD, and DisGeNET databases and then submitted to the STRING to establish the protein-protein interaction (PPI) network. The co-bioinformatics analysis was conducted by Metascape. The active ingredients of BSYQ decoction were screened from TCMSP, ETCM, BATMAN-TCM databases, and HPLC/MS experiment. The corresponding targets were predicted based on TCMSP, ETCM, and BATMAN-TCM databases. The shared targets for asthma and IPF treatment were recognized, and further GO and KEGG analyses were conducted with the DAVID platform. Finally, molecule docking via Autodock Vina was employed to predict the potential binding mode between core potential compounds and targets.

RESULTS: Finally, 1333 asthma-related targets and 404 IPF-related proteins were retrieved, 120 were overlapped between them, and many of the asthma-related proteins fall into the same statistically significant GO terms with IPF. Moreover, 116 active ingredients of BSYQ decoction were acquired, and 1535 corresponding targets were retrieved. Eighty-three potential compounds and 56 potential targets were recognized for both asthma and IPF treatment. GO and KEGG analysis indicated that the inflammation response, cytokine production, leukocyte differentiation, oxygen level response, etc., were the common pathological processes in asthma and IPF, which were regulated by BSYQ decoction. Molecule docking further predicted the potential binding modes between the core potential compounds and targets.

CONCLUSION: The current study successfully clarified the complex molecule links between asthma and IPF and found the potential common targets. Then we demonstrated the efficacy of BSYQ decoction for asthma and IPF treatment from the angle of network pharmacology, which may provide valuable references for further studies and clinical use.

PMID:35672815 | DOI:10.1186/s12906-022-03637-7

Respir Res. 2022 Jun 7;23(1):147. doi: 10.1186/s12931-022-02067-w.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is associated with increased expression of cyclin-dependent kinase inhibitors such as p16 and p21, and subsequent induction of cell cycle arrest, cellular senescence, and pro-fibrotic gene expression. We sought to link p16-expression with a diagnosis of IPF or other fibrotic interstitial lung diseases (ILDs), radiographic pattern, senescent foci-specific gene expression, antifibrotic therapy response, and lung transplant (LTx)-free survival.

METHODS: Eighty-six cases of fibrosing ILD were identified with surgical lung biopsy. Immunohistochemistry for p16 was performed on sections with the most active fibrosis. p16-positive foci (loose collection of p16-positive fibroblasts with overlying p16-positive epithelium) were identified on digital slides and quantified. Cases were scored as p16-low (≤ 2.1 foci per 100 mm2) or p16-high (> 2.1 foci per 100 mm2). Twenty-four areas including senescent foci, fibrotic and normal areas were characterized using in situ RNA expression analysis with digital spatial profiling (DSP) in selected cases.

RESULTS: The presence of p16-positive foci was specific for the diagnosis of IPF, where 50% of cases expressed any level of p16 and 26% were p16-high. There was no relationship between radiographic pattern and p16 expression. However, there was increased expression of cyclin-dependent kinase inhibitors, collagens and matrix remodeling genes within p16-positive foci, and cases with high p16 expression had shorter LTx-free survival. On the other hand, antifibrotic therapy was significantly protective. DSP demonstrated that fibroblastic foci exhibit transcriptional features clearly distinct from that of normal-looking and even fibrotic areas.

CONCLUSIONS: We demonstrated the potential clinical applicability of a standardized quantification of p16-positive fibroblastic foci. This method identifies an IPF phenotype associated with foci-specific upregulation of senescence-associated and matrix remodeling gene expression. While these patients have reduced LTx-free survival, good response to antifibrotic therapies was observed in those who were treated.

PMID:35672770 | DOI:10.1186/s12931-022-02067-w

J Innate Immun. 2022 Jun 7:1-13. doi: 10.1159/000524693. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a type of idiopathic interstitial pneumonia with a poor clinical prognosis. Increasing evidence has demonstrated that epithelial-mesenchymal transition (EMT) contributes to the production of pathogenic myofibroblasts and plays a pivotal role in the development of pulmonary fibrosis. Mannan-binding lectin (MBL) is a soluble calcium-dependent complement molecule. Several studies have reported associations between serum MBL levels and lung diseases; however, the effect of MBL on IPF remains unknown. The present study observed aggravated pulmonary fibrosis in bleomycin-treated MBL-/- mice compared with their wild-type counterparts. Lung tissues from bleomycin-treated MBL-/- mice displayed a more severe EMT phenotype. In vitro studies determined that MBL inhibited the EMT process through attenuating store-operated calcium entry (SOCE) signaling. It was further demonstrated that MBL promoted the ubiquitination of Orai1, an essential component of SOCE, via pyruvate dehydrogenase kinase 1 (PDK1)-serum glucocorticoid-regulated kinase 1 signaling. PDK1 inhibition abolished the MBL-mediated regulation of SOCE activity and the EMT process. Notably, biochemical analysis showed that MBL interacted with PDK1 and contributed to PDK1 ubiquitination. In summary, the present findings suggested that MBL limited the EMT phenotype in human alveolar epithelial cells through regulation of SOCE, and MBL could be recognized as a potential therapeutic target for IPF.

PMID:35671705 | DOI:10.1159/000524693

Am J Respir Crit Care Med. 2022 Jun 7. doi: 10.1164/rccm.202206-1058LE. Online ahead of print.

NO ABSTRACT

PMID:35671482 | DOI:10.1164/rccm.202206-1058LE

Am J Respir Crit Care Med. 2022 Jun 7. doi: 10.1164/rccm.202205-0989LE. Online ahead of print.

NO ABSTRACT

PMID:35671476 | DOI:10.1164/rccm.202205-0989LE

Proc Natl Acad Sci U S A. 2022 Jun 14;119(24):e2201707119. doi: 10.1073/pnas.2201707119. Epub 2022 Jun 7.

ABSTRACT

A number of inflammatory lung diseases, including chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, and pneumonia, are modulated by WNT/β-catenin signaling. However, the underlying molecular mechanisms remain unclear. Here, starting with a forward genetic screen in mouse, we identify the WNT coreceptor Related to receptor tyrosine kinase (RYK) acting in mesenchymal tissues as a cell survival and antiinflammatory modulator. Ryk mutant mice exhibit lung hypoplasia and inflammation as well as alveolar simplification due to defective secondary septation, and deletion of Ryk specifically in mesenchymal cells also leads to these phenotypes. By analyzing the transcriptome of wild-type and mutant lungs, we observed the up-regulation of proapoptotic and inflammatory genes whose expression can be repressed by WNT/RYK signaling in vitro. Moreover, mesenchymal Ryk deletion at postnatal and adult stages can also lead to lung inflammation, thus indicating a continued role for WNT/RYK signaling in homeostasis. Our results indicate that RYK signaling through β-catenin and Nuclear Factor kappa B (NF-κB) is part of a safeguard mechanism against mesenchymal cell death, excessive inflammatory cytokine production, and inflammatory cell recruitment and accumulation. Notably, RYK expression is down-regulated in the stromal cells of pneumonitis patient lungs. Altogether, our data reveal that RYK signaling plays critical roles as an antiinflammatory modulator during lung development and homeostasis and provide an animal model to further investigate the etiology of, and therapeutic approaches to, inflammatory lung diseases.

PMID:35671428 | DOI:10.1073/pnas.2201707119

Minerva Med. 2022 Jun 7. doi: 10.23736/S0026-4806.22.08018-1. Online ahead of print.

ABSTRACT

BACKGROUND: Cardiovascular diseases are frequent in idiopathic pulmonary fibrosis (IPF) and impact on survival. We investigated the association of coronary artery calcium (CAC) score at IPF diagnosis and during mid-term follow-up, with adverse cardiovascular events and all-cause mortality.

METHODS: Consecutive patients with IPF were retrospectively analyzed. Demographic data, smoking history, comorbidities and pulmonary function tests (PFTs) were recorded. All patients had at least two chest high resolution computed tomography (HRCT) performed 2 years apart. The total CAC score and visual fibrotic score were calculated and all clinically significant cardiovascular events and deaths were reported.

RESULTS: The population consisted of 79 patients (57 male, mean age 74.4 ± 7.6 years); 67% of patients had a history of smoking, 48% of hypertension, 37% of dyslipidemia and 22.8% of diabetes. The visual score was 21.28 ± 7.99% at T0 and 26.54 ± 9.34% at T1, respectively (T1-T0 5.26 ± 6.13%, p< 0.001). CAC score at T0 and at T1 was 537.93 ± 839.94 and 759.98 ± 1027.6, respectively (T1-T0 224.66 ± 406.87, p< 0.001). Mean follow-up time was 2.47±1.1 years. On multivariate analysis, male sex (HR 3.58, 95% CI 1.14-11.2) and CAC score at T0 (HR 1.04, 95% CI 1.01-1.07) correlated with mortality and cardiovascular events. CAC score at T0 ≥405 showed 82% sensitivity and 100% specificity for predicting mortality and adverse cardiovascular events.

CONCLUSIONS: IPF patients with a CAC score at diagnosis ≥405 have a poor prognosis over a midterm follow-up. A higher CAC score is associated with mortality and cardiovascular events.

PMID:35671002 | DOI:10.23736/S0026-4806.22.08018-1

Phytomedicine. 2022 May 21;103:154187. doi: 10.1016/j.phymed.2022.154187. Online ahead of print.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic disease of unknown aetiology with limited effective treatment options. It is important to explore novel therapeutic targets and develop potential drugs for IPF.

PURPOSE: The aim of the present study was to analyse nontargeted plasma metabolites in patients with IPF and investigate whether cannabinoid receptor (CB2) activation mediates the antifibrotic effect of icariin (ICA).

METHODS: We used an untargeted metabolomics method to detect the global metabolic profiles in the plasma of stable IPF patients and patients with stable chronic obstructive pulmonary disease (COPD), as well as healthy subjects. The untargeted liquid chromatography-mass spectrometry (LC-MS) analysis revealed that IPF showed differential metabolites and perturbed signalling pathways. ICA is pharmacologically bioactive and possesses extensive therapeutic capacities such as osteoprotective, neuroprotective, cardiovascular protective, anti-cancer, anti-inflammation and reproductive function. Therefore, ICA was administered to a pulmonary fibrosis rat model for 4 weeks and then the effect of ICA on pulmonary fibrosis was examined by dissection and histology.

RESULTS: The metabolites in the plasma were determined by untargeted LC-MS. An unsupervised principal component analysis (PCA) was used to observe the distribution of each sample, and a supervised partial least squares-discriminant analysis (PLS-DA) and orthogonal partial least squares-discriminant analysis (OPLS-DA) results showed that there was significant separation between any two groups. ROC curve analyses revealed that 8 metabolites with high AUCs above 0.7 between the three groups of plasma samples. Pathway enrichment analysis revealed that 3 metabolites are involved in retrograde endocannabinoid signalling. Meanwhile, Retrograde endocannabinoid signalling was identified significantly different in IPF group from other groups by Kyoto encyclopedia of Genes and Genomes (KEGG) pathway analysis, and then we further confirmed the endocannabinoid signalling by detecting the expression of the main receptors in bleomycin-induced pulmonary fibrosis, COPD rat model and normal rats. Consistent with previous studies, we found that the elevation of CB1 and CB2 in the lung tissues could be a signature of the pulmonary fibrosis rat model. Importantly, ICA may alleviate bleomycin-induced lung injury by decreasing CB1 and CB2 expression in the bleomycin-induced rat model.

CONCLUSION: Taken together, we measured the global metabolic profile of IPF patients and identified CB2 as a novel potential target. ICA treatment demonstrated outstanding therapeutic effects on bleomycin-induced pulmonary fibrosis and targeting on CB2 may be the main underlying mechanism. ICA is a promising drug candidate to cure pulmonary fibrosis and mediate antagonists of the CB2 receptor.

PMID:35667261 | DOI:10.1016/j.phymed.2022.154187

J Med Chem. 2022 Jun 6. doi: 10.1021/acs.jmedchem.2c00458. Online ahead of print.

ABSTRACT

Our previous research demonstrated that phosphodiesterase-1 (PDE1) could work as a potential target against idiopathic pulmonary fibrosis. Nimodipine, a calcium antagonist commonly used to improve hypertension, was reported to have inhibition against PDE1. Herein, a series of nimodipine analogues were discovered as novel selective and potent PDE1 inhibitors after structural modifications. Compound 2g exhibited excellent inhibitory activity against PDE1C (IC50 = 10 nM), high selectivity over other PDEs except for PDE4, and weak calcium channel antagonistic activity. Administration of compound 2g exhibited remarkable therapeutic effects in a rat model of pulmonary fibrosis induced by bleomycin and prevented myofibroblast differentiation induced by TGF-β1. The expressions of PDE1B and PDE1C were found to be increased and concentrated in the focus of fibrosis. Compound 2g increased the levels of 3',5'-cyclic adenosine monophosphate (cAMP) and 3',5'-cyclic guanosine monophosphate (cGMP) in the lungs of rats with pulmonary fibrosis, supporting the fact that the anti-fibrosis effects of 2g were through the regulation of cAMP and cGMP.

PMID:35666471 | DOI:10.1021/acs.jmedchem.2c00458

Medicine (Baltimore). 2022 Jun 3;101(22):e29232. doi: 10.1097/MD.0000000000029232.

ABSTRACT

INTRODUCTION: A subgroup analysis of the CAPACITY and ASCEND trials showed that pirfenidone use beyond disease progression reduced the risk of subsequent forced vital capacity (FVC) decline and death. Our study aimed to compare the efficacy and safety of nintedanib with or without pirfenidone for patients with idiopathic pulmonary fibrosis (IPF) who experienced disease progression during previous pirfenidone therapy.

METHODS: In this randomized, open-label, selection design phase II trial, patients with IPF and a ≥5% relative decline in FVC within 6 months of the pirfenidone administration period were randomly assigned to nintedanib (switch group) or nintedanib plus pirfenidone (combination group). The primary endpoint was the incidence of a ≥5% relative decline in FVC or death during the first 6 months.

RESULTS: Only 7 patients were enrolled (4 in the switch group and 3 in the combination group). Although the switch group continued with nintedanib for 1 year or more, 2 patients (66.7%) in the combination group discontinued nintedanib within 6 months due to severe adverse events. Given the slow case registration and safety concerns in the combination group, the trial was terminated without extending the registration. The incidence of a ≥5% relative decline in FVC during the first 6 months was 50.0% in the switch group and 66.7% in the combination group. There were no deaths during the observation period.

CONCLUSIONS: Clinical trials verifying the use of pirfenidone after disease progression in IPF may be difficult to enroll patients. Definitive conclusions on both safety and efficacy cannot be drawn from the results of this study alone.

TRIAL REGISTRATION: UMIN Clinical Trial Registry; registration number, UMIN000019436; date of first registration, 21/10/2015; https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000022471.

PMID:35665728 | DOI:10.1097/MD.0000000000029232

ACS Omega. 2022 May 17;7(21):17658-17669. doi: 10.1021/acsomega.2c00535. eCollection 2022 May 31.

ABSTRACT

αVβ6 Integrin plays a fundamental role in the activation of transforming growth factor-β (TGF-β), the major profibrotic mediator; for this reason, αVβ6 ligands have recently been forwarded to clinical phases for the therapy of fibrotic diseases. Herein, we report the synthesis and in vitro biological evaluation as antifibrotic agents of three new covalent conjugates, constituted by c(AmpLRGDL), an αVβ6 integrin-recognizing small cyclopeptide, and nintedanib, a tyrosine kinase inhibitor approved for idiopathic pulmonary fibrosis (IPF) treatment. One of these conjugates recapitulates optimal in vitro antifibrotic properties of the two active units. The integrin ligand portion within the conjugate plays a role in inhibiting profibrotic stimuli, potentiating the nintedanib effect and favoring the selective uptake of the conjugate in cells overexpressing αVβ6 integrin. These results may open a new perspective on the development of dual conjugates in the targeted therapy of IPF.

PMID:35664627 | PMC:PMC9161413 | DOI:10.1021/acsomega.2c00535

Front Pharmacol. 2022 May 19;13:848263. doi: 10.3389/fphar.2022.848263. eCollection 2022.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive disease, and its occurrence and development are mediated by cellular senescence. Drugs targeting senescent cells seem like a promising and efficacious strategy for IPF treatment. Previous studies have illustrated that pentoxifylline (PTX) may play a certain role in inhibiting pulmonary fibrosis and combating cellular senescence. In this study, we demonstrated that PTX administration inhibits pulmonary fibrosis development and cellular senescence in the bleomycin (BLM)-induced IPF mice model. Moreover, the expression levels of fibrosis-related genes and senescence-related genes in mice lung tissue and primary pulmonary fibroblasts illustrated lung fibroblasts' vital role in these two processes. And the curative effect of PTX was completed mainly by acting on lung fibroblasts. Besides, during the whole treatment, delayed initiation or advanced halt of PTX administration would influence its effectiveness in reducing fibrotic and senescent traits in various degrees, and the latter influenced more. We further determined that a long period of PTX administration could bring noticeable benefits to mice in recovering BLM-induced lung fibrosis and suppressing age-associated cellular senescence. Moreover, it was still effective when PTX administration was used to treat senescent human fibroblasts. Thus, our findings manifested that PTX therapy is an efficient remedy for pulmonary fibrosis by suppressing cellular senescence.

PMID:35662697 | PMC:PMC9160723 | DOI:10.3389/fphar.2022.848263

Pharmacol Res. 2022 Jun 1:106286. doi: 10.1016/j.phrs.2022.106286. Online ahead of print.

ABSTRACT

Pulmonary fibrosis (PF) is the pathological change of end-stage interstitial lung diseases with high mortality and limited therapeutic options. Lung macrophages have distinct subsets with divergent functions, and play critical roles in the pathogenesis of PF. In this study, integrative analysis of lung single-cell and bulk RNA-seq data from patients with fibrotic hypersensitivity pneumonitis and idiopathic pulmonary fibrosis was utilized to identify particular macrophage subset during the development of PF. We find a specific macrophage subpopulation highly expressing PLA2G7 in fibrotic lungs. We performed additional single-cell RNA-seq analysis to identify analogous macrophage population in bleomycin (BLM)-induced mouse pulmonary fibrosis models. By in vitro and in vivo experiments, we further reveal the pro-fibrotic role for this PLA2G7high macrophage subset in fibroblast-to-myofibroblast transition (FMT) during pulmonary fibrosis. PLA2G7 promotes FMT via LPC/ATX/LPA/LPA2 axis in macrophages. Moreover, PLA2G7 is regulated by STAT1, and pharmacological inhibition of PLA2G7 by Darapladib ameliorates pulmonary fibrosis in BLM-induced mice. The results of this study support the view that PLA2G7high macrophage subpopulation contributes importantly to the pathogenesis of PF, which provides a potential way for targeted therapy.

PMID:35662628 | DOI:10.1016/j.phrs.2022.106286