J Clin Lab Anal. 2022 Oct 17:e24734. doi: 10.1002/jcla.24734. Online ahead of print.

ABSTRACT

BACKGROUND: Higher detection of interstitial pneumonia with autoimmune features (IPAF), and idiopathic pulmonary fibrosis (IPF), has significant diagnostic and therapeutic implications. Some matrix metalloproteinases (MMPs) have become reliable diagnostic biomarkers in IPAF and IPF in previous studies, yet relevant reliability remains to be recognized.

MATERIALS AND METHODS: In this study, 36 ILDs patients, including 31 IPAF patients (Mean ± SD, 50.20 ± 5.10 years; 16 [51.6%] females) and five IPF patients (Mean ± SD, 61.20 ± 6.73 years; one [20.0%] females) were retrospectively enrolled. Serial serum samples were collected from patients with IPAF and IPF between January 2019 and December 2020. Notably, Serum MMPs levels were measured by U-PLEX Biomarker Group 1(Human) Multiplex Assays (MSD, USA).

RESULTS: A combination of MMPs and combinatorial biomarkers was strongly associated with clinical subjects in this study (AUC, 0.597 for Stability vs. Improvement and 0.756 for Stability vs. Exacerbation). Importantly, the AUC of MMP-12 reaches 0.730 (p < 0.05, Stability AUC vs. Improvement AUC) while MMP-13 reaches 0.741 (p < 0.05, Stability AUC vs. Exacerbation AUC) showed better performance than other MMPs in two comparisons.

CONCLUSIONS: Clinical risk factors and MMPs are strongly associated with either stratification of the disease of progression of IPAF or in two IPAF and IPF independent cohorts. To our knowledge, this is the first to illustrate that MMP-12 and MMP-13 may be expected to become typical promising biomarkers in Improvement - IPAF and Exacerbation - IPAF, respectively.

PMID:36250225 | DOI:10.1002/jcla.24734

Front Immunol. 2022 Sep 29;13:976512. doi: 10.3389/fimmu.2022.976512. eCollection 2022.

ABSTRACT

COVID-19 prognoses suggests that a proportion of patients develop fibrosis, but there is no evidence to indicate whether patients have progression of mesenchymal transition (MT) in the lungs. The role of MT during the COVID-19 pandemic remains poorly understood. Using single-cell RNA sequencing, we profiled the transcriptomes of cells from the lungs of healthy individuals (n = 45), COVID-19 patients (n = 58), and idiopathic pulmonary fibrosis (IPF) patients (n = 64) human lungs to map the entire MT change. This analysis enabled us to map all high-resolution matrix-producing cells and identify distinct subpopulations of endothelial cells (ECs) and epithelial cells as the primary cellular sources of MT clusters during COVID-19. For the first time, we have identied early and late subgroups of endothelial mesenchymal transition (EndMT) and epithelial-mesenchymal transition (EMT) using analysis of public databases for single-cell sequencing. We assessed epithelial subgroups by age, smoking status, and gender, and the data suggest that the proportional changes in EMT in COVID-19 are statistically significant. Further enumeration of early and late EMT suggests a correlation between invasive genes and COVID-19. Finally, EndMT is upregulated in COVID-19 patients and enriched for more inflammatory cytokines. Further, by classifying EndMT as early or late stages, we found that early EndMT was positively correlated with entry factors but this was not true for late EndMT. Exploring the MT state of may help to mitigate the fibrosis impact of SARS-CoV-2 infection.

PMID:36248845 | PMC:PMC9558222 | DOI:10.3389/fimmu.2022.976512

Can Respir J. 2022 Oct 4;2022:9663354. doi: 10.1155/2022/9663354. eCollection 2022.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic, irreversible, and progressive interstitial lung disease characterized by recurrent alveolar epithelial cell injury, fibroblast hyperproliferation, and cumulative deposition of extracellular matrix leading to alveolar destruction in the lungs. Mitotic arrest deficient 2 like 1 (MAD2L1) is a component of the mitotic spindle assembly checkpoint that prevents the onset of anaphase until all chromosomes are properly aligned at metaphase and is a potential therapeutic target in cancers. However, the role of MAD2L1 in pulmonary fibrosis has not been explored. We analyzed the expression of MAD2L1 in lung tissues from control subjects, IPF patients, and mice with bleomycin-induced fibrosis via IHC, qRT-PCR, and Western blot analysis. We examined the roles of MAD2L1 in ROS production, mitochondrial function, cell senescence, and the establishment of a profibrotic microenvironment. We found that MAD2L1 was highly upregulated in alveolar epithelial cells in fibrotic lung tissues from both patients with IPF and mice with bleomycin-induced fibrosis. Loss of MAD2L1 expression or activity led to decreases of cell viability and proliferation in A549 cells. Subsequent mechanistic investigation demonstrated that inhibition of MAD2L1 damaged mitochondria, which led to augmented ROS production and cellular senescence, and thus promoted the establishment of a profibrotic microenvironment. Taken together, these results reveal that alleviation of alveolar epithelial cell mitochondrial damage arising from augmentation of MAD2L1 may be a novel therapeutic strategy for mitigating pulmonary fibrosis.

PMID:36247080 | PMC:PMC9553670 | DOI:10.1155/2022/9663354

J Med Invest. 2022;69(3.4):196-203. doi: 10.2152/jmi.69.196.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is the most common idiopathic interstitial pneumonias. Lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P) are signaling lipids that evoke growth factor-like responses to many cells. Recent studies revealed the involvement of LPA and S1P in the pathology of IPF. In this study, we determined LPA, S1P and ceramide 1-phosphate (C1P) in peripheral blood plasma of IPF patients, and examined correlation to the vital capacity of lung (VC), an indicator of development of fibrosis. Blood plasma samples were taken from eleven patients with IPF and seven healthy volunteers. The lipids of the sample were extracted and subjected to liquid chromatography-tandem mass spectrometry for analysis. Results showed that there is a significant negative correlation between VC and plasma LPA levels, indicating that IPF patients with advanced fibrosis had higher concentration of LPA in their plasma. Average of S1P levels were significantly higher in IPF patients than those in healthy subjects. Although it is not statistically significant, a similar correlation trend that observed in LPA levels also found between VC and S1P levels. These results indicated that plasma LPA and S1P may be associated with deterioration of pulmonary function of IPF patients. J. Med. Invest. 69 : 196-203, August, 2022.

PMID:36244770 | DOI:10.2152/jmi.69.196

Curr Top Microbiol Immunol. 2022;436:437-466. doi: 10.1007/978-3-031-06566-8_19.

ABSTRACT

A number of different experimental models using both non-selective and selective PI3K inhibitors have shown that many pathogenic steps of respiratory disorders, such as bronchial asthma, Chronic Obstructive Pulmonary Disease (COPD), Idiopathic Pulmonary Fibrosis (IPF), Acute Respiratory Distress Syndrome (ARDS) and Lung Cancer (LC) are, at least in part, regulated by the PI3K signaling pathway, suggesting that the inhibition of PI3K could represent an ideal therapeutic target for the treatment of respiratory diseases. This chapter summarizes the current state of the therapeutic strategies aimed to exploit the inhibition of PI3K in this context. In animal models of asthma, selective δ and γ inhibitors have shown to be effective, and when administered by inhalation, reasonably safe. Nevertheless, very few clinical trials have been performed so far. The efficacy of current traditional therapies for allergic bronchial asthma has likely diminished the need for new alternative treatments. Surprisingly, in COPD, where instead there is an urgent need for new and more effective therapeutic approaches, the number of clinical studies is still low and not capable yet, with the exception for an acceptable safety profile, to show a significant improvement of clinical outcomes. In IPF, a disease with a disappointing prognosis, PI3K inhibitors have been bound to a FAP ligand with the aim to selectively target myofibroblasts, showing to significantly reduce collagen production and the development of lung fibrosis in an animal model of lung fibrosis. Due to its role in cell activation and cell replication, the PI3K pathway is obviously largely involved in lung cancer. Several studies, currently ongoing, are testing the effect of PI3K inhibitors mainly in NSCLC. Some evidence in the treatment of cancer patients suggests the possibility that PI3K inhibitors may enhance the response to conventional treatment. The involvement of PI3Kδ in the modulation of airway neutrophil recruitment and bronchial epithelial functional alterations also suggest a potential role in the treatment of ARDS, but at the current state the ongoing trials are aimed to the treatment of ARDS in COVID-19 patients. In general, few clinical trials investigating PI3K inhibitors in respiratory disorders have been performed so far. This relatively new approach of treatment is just at its beginning and certainly needs further efforts and additional studies.

PMID:36243856 | DOI:10.1007/978-3-031-06566-8_19

Int J Mol Sci. 2022 Oct 8;23(19):11946. doi: 10.3390/ijms231911946.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive, chronic, interstitial lung disease with a poor prognosis. Although specific anti-fibrotic medications are now available, the median survival time following diagnosis remains very low, and new therapies are urgently needed. To uncover novel therapeutic targets, we examined how biochemical properties of the fibrotic lung are different from the healthy lung. Previous work identified lactate as a metabolite that is upregulated in IPF lung tissue. Importantly, inhibition of the enzyme responsible for lactate production prevents fibrosis in vivo. Further studies revealed that fibrotic lesions of the lung experience a significant decline in tissue pH, likely due to the overproduction of lactate. It is not entirely clear how cells in the lung respond to changes in extracellular pH, but a family of proton sensing G-protein coupled receptors has been shown to be activated by reductions in extracellular pH. This work examines the expression profiles of proton sensing GPCRs in non-fibrotic and IPF-derived primary human lung fibroblasts. We identify TDAG8 as a proton sensing GPCR that is upregulated in IPF fibroblasts and that knockdown of TDAG8 dampens myofibroblast differentiation. To our surprise, BTB, a proposed positive allosteric modulator of TDAG8, inhibits myofibroblast differentiation. Our data suggest that BTB does not require TDAG8 to inhibit myofibroblast differentiation, but rather inhibits myofibroblast differentiation through suppression of RhoA mediated signaling. Our work highlights the therapeutic potential of BTB as an anti-fibrotic treatment and expands upon the importance of RhoA-mediated signaling pathways in the context of myofibroblast differentiation. Furthermore, this works also suggests that TDAG8 inhibition may have therapeutic relevance in the treatment of IPF.

PMID:36233248 | DOI:10.3390/ijms231911946

Int J Mol Sci. 2022 Sep 28;23(19):11443. doi: 10.3390/ijms231911443.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive, chronic, and ultimately fatal diffuse parenchymal lung disease. The molecular mechanisms of fibrosis in IPF patients are not fully understood and there is a lack of effective treatments. For decades, different types of drugs such as immunosuppressants and antioxidants have been tested, usually with unsuccessful results. Although two antifibrotic drugs (Nintedanib and Pirfenidone) are approved and used for the treatment of IPF, side effects are common, and they only slow down disease progression without improving patients' survival. Macrophages are central to lung homeostasis, wound healing, and injury. Depending on the stimulus in the microenvironment, macrophages may contribute to fibrosis, but also, they may play a role in the amelioration of fibrosis. In this review, we explore the role of macrophages in IPF in relation to the fibrotic processes, epithelial-mesenchymal transition (EMT), and their crosstalk with resident and recruited cells and we emphasized the importance of macrophages in finding new treatments.

PMID:36232756 | DOI:10.3390/ijms231911443

Int J Mol Sci. 2022 Sep 23;23(19):11212. doi: 10.3390/ijms231911212.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial fibrotic disease that leads to disability and death within 5 years of diagnosis. Pulmonary fibrosis is a disease with a multifactorial etiology. The concept of aberrant regeneration of the pulmonary epithelium reveals the pathogenesis of IPF, according to which repeated damage and death of alveolar epithelial cells is the main mechanism leading to the development of progressive IPF. Cell death provokes the migration, proliferation and activation of fibroblasts, which overproduce extracellular matrix, resulting in fibrotic deformity of the lung tissue. Mesenchymal stem cells (MSCs) and extracellular vesicles (EVs) are promising therapies for pulmonary fibrosis. MSCs, and EVs derived from MSCs, modulate the activity of immune cells, inhibit the expression of profibrotic genes, reduce collagen deposition and promote the repair of damaged lung tissue. This review considers the molecular mechanisms of the development of IPF and the multifaceted role of MSCs in the therapy of IPF. Currently, EVs-MSCs are regarded as a promising cell-free therapy tool, so in this review we discuss the results available to date of the use of EVs-MSCs for lung tissue repair.

PMID:36232511 | DOI:10.3390/ijms231911212

Int J Mol Sci. 2022 Sep 20;23(19):11047. doi: 10.3390/ijms231911047.

ABSTRACT

Communication between neighboring or distant cells is made through a complex network that includes extracellular vesicles (EVs). Exosomes, which are a subgroup of EVs, are released from most cell types and have been found in biological fluids such as urine, plasma, and airway secretions like bronchoalveolar lavage (BAL), nasal lavage, saliva, and sputum. Mainly, the cargo exosomes are enriched with mRNAs and microRNAs (miRNAs), which can be transferred to a recipient cell consequently modifying and redirecting its biological function. The effects of miRNAs derive from their role as gene expression regulators by repressing or degrading their target mRNAs. Nowadays, various types of research are focused on evaluating the potential of exosomal miRNAs as biomarkers for the prognosis and diagnosis of different pathologies. Nevertheless, there are few reports on their role in the pathophysiology of idiopathic pulmonary fibrosis (IPF), a chronic lung disease characterized by progressive lung scarring with no cure. In this review, we focus on the role and effect of exosomal miRNAs as intercellular communicators in the onset and progression of IPF, as well as discussing their potential utility as therapeutic agents for the treatment of this disease.

PMID:36232350 | DOI:10.3390/ijms231911047

Cells. 2022 Sep 27;11(19):3014. doi: 10.3390/cells11193014.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is an aging-associated disease characterized by exacerbated extracellular matrix deposition that disrupts oxygen exchange. Hypoxia and its transcription factors (HIF-1α and 2α) influence numerous circuits that could perpetuate fibrosis by increasing myofibroblasts differentiation and by promoting extracellular matrix accumulation. Therefore, this work aimed to elucidate the signature of hypoxia in the transcriptomic circuitry of IPF-derived fibroblasts. To determine this transcriptomic signature, a gene expression analysis with six lines of lung fibroblasts under normoxia or hypoxia was performed: three cell lines were derived from patients with IPF, and three were from healthy donors, a total of 36 replicates. We used the Clariom D platform, which allows us to evaluate a huge number of transcripts, to analyze the response to hypoxia in both controls and IPF. The control's response is greater by the number of genes and complexity. In the search for specific genes responsible for the IPF fibroblast phenotype, nineteen dysregulated genes were found in lung fibroblasts from IPF patients in hypoxia (nine upregulated and ten downregulated). In this sense, the signaling pathways revealed to be affected in the pulmonary fibroblasts of patients with IPF may represent an adaptation to chronic hypoxia.

PMID:36230977 | DOI:10.3390/cells11193014

Cells. 2022 Sep 20;11(19):2938. doi: 10.3390/cells11192938.

ABSTRACT

Hypoxia and hypoxia-inducible factors (HIFs) are essential in regulating several cellular processes, such as survival, differentiation, and the cell cycle; this adaptation is orchestrated in a complex way. In this review, we focused on the impact of hypoxia in the physiopathology of idiopathic pulmonary fibrosis (IPF) related to lung development, regeneration, and repair. There is robust evidence that the responses of HIF-1α and -2α differ; HIF-1α participates mainly in the acute phase of the response to hypoxia, and HIF-2α in the chronic phase. The analysis of their structure and of different studies showed a high specificity according to the tissue and the process involved. We propose that hypoxia-inducible transcription factor 2a (HIF-2α) is part of the persistent aberrant regeneration associated with developing IPF.

PMID:36230900 | DOI:10.3390/cells11192938

Am J Respir Cell Mol Biol. 2022 Oct 13. doi: 10.1165/rcmb.2022-0021OC. Online ahead of print.

ABSTRACT

Pro-fibrotic and pro-homeostatic macrophage phenotypes remain ill-defined, both in vivo and in vitro impeding successful development of drugs that reprogram macrophages as an attractive therapeutic approach to manage fibrotic disease. The goal to of this study was to reveal pro-fibrotic and pro-homeostatic macrophage phenotypes which could guide the design of new therapeutic approaches targeting macrophages to treat fibrotic disease. We used nintedanib, a broad kinase inhibitor, approved for idiopathic pulmonary fibrosis (IPF) to dissect lung macrophage phenotypes during fibrosis-linked inflammation by combining in vivo and in vitro bulk and single cell RNA sequencing approaches. In the bleomycin model, nintedanib drove expression of IL-4/IL-13 associated genes important for tissue regeneration and repair at early and late time points in lung macrophages. These findings were replicated in vitro in mouse primary bone marrow derived macrophages exposed to IL-4/IL-13 and nintedanib. In addition, nintedanib promoted expression of IL-4/IL-13 pathway genes in human macrophages in vitro. The molecular mechanism was connected to inhibition of the CSF1 receptor (CSF1R) in both human and mouse macrophages. Moreover, nintedanib counterbalanced the effects of TNF on IL-4/IL-13 in macrophages to promote expression of IL-4/IL-13 regulated tissue repair genes in fibrotic contexts in vivo and in vitro. Our study demonstrates the one of nintedanib's anti-fibrotic mechanisms is to increase IL-4 signaling in macrophages through inhibition of CSF1 receptor resulting in promotion of tissue repair phenotypes.

PMID:36227799 | DOI:10.1165/rcmb.2022-0021OC

J Food Biochem. 2022 Oct 13:e14483. doi: 10.1111/jfbc.14483. Online ahead of print.

ABSTRACT

EZY-1 is an antifibrosis peptide purified from Eucheuma. In this study, we explored the acute toxicology of EZY-1 and the signaling pathways involved in its antifibrotic role. The mouse model of pulmonary fibrosis was induced by bleomycin. Pathological changes in lung tissue could be effectively inhibited by EZY-1. Acute toxicity and cell proliferation tests indicated that EZY-1 had no apparent toxicity to mice and cells. We identified proteins that could bind directly to EZY-1 in vitro on the basis of liquid chromatography-tandem mass spectrometry and bioinformatics analysis. EZY-1 inhibited pulmonary fibrosis via Wnt/β-catenin, transforming growth factor (TGF)-β/Smad, phosphoinositide 3-kinase/protein kinase B/ mammalian target of rapamycin, and activator of transcription 3 and Janus kinase 2/signal transducer pathways. A transwell micropore experiment showed that EZY-1 could inhibit cell migration and invasion. Western blotting analysis on transforming growth factor-β1 (TGF-β1)-induced A549 pulmonary fibrosis cell model suggested that EZY-1 could downregulate p-Smad3 (Ser423/Ser425), Smad4, β-catenin, vimentin, and N-cadherin expression. ELISA showed that EZY-1 could inhibit collagen-I secretion. EZY-1 alleviated idiopathic pulmonary fibrosis (IPF) through regulating TGF-β/Smad pathways, epithelial-mesenchymal transition processes, and collagen secretion, which provides a potential foundation for theoretical development of EZY-1 as a potential drug against IPF. PRACTICAL APPLICATIONS: We isolated a new 16-amino-acid peptide derived from the polypeptide extract of Eucheuma, named EZY-1. In vitro and in vivo assays show peptide EZY-1 is safe. The EZY-1 peptide alleviates IPF at lower doses than pirfenidone. EZY-1 alleviated idiopathic pulmonary fibrosis (IPF) through regulating TGF-β/Smad pathways, epithelial-mesenchymal transition (EMT) processes, and collagen secretion, which provides a theoretical basis for the development of EZY-1 as a potential drug against IPF.

PMID:36226766 | DOI:10.1111/jfbc.14483

Pulm Circ. 2022 Oct 1;12(4):e12141. doi: 10.1002/pul2.12141. eCollection 2022 Oct.

ABSTRACT

Pulmonary hypertension (PH) complicates the treatment of interstitial lung disease (ILD) patients resulting in poor functional status and worse outcomes. Early recognition of PH in ILD is important for initiating therapy and considering lung transplantation. However, no standard exists regarding which patients to screen for PH-ILD or the optimal method to do so. The aim of this study was to create a risk assessment tool that could reliably predict PH in ILD patients. We developed a PH-ILD Detection tool that incorporated history, exam, 6-min walk distance, diffusion capacity for carbon monoxide, chest imaging, and cardiac biomarkers to create an eight-component score. This tool was analyzed retrospectively in 154 ILD patients where each patient was given a score ranging from 0 to 12. The sensitivity (SN) and specificity (SP) of the PH-ILD Detection tool and an area-under-the-curve (AUC) were calculated. In this cohort, 74 patients (48.1%) had PH-ILD. A score of ≥6 on the PH-ILD Detection tool was associated with a diagnosis of PH-ILD (SN: 86.5%; SP: 86.3%; area-under-the-curve: 0.920, p < 0.001). The PH-ILD Detection tool provides high SN and SP for detecting PH in ILD patients. With confirmation in larger cohorts, this tool could improve the diagnosis of PH in ILD and may suggest further testing with right heart catheterization and earlier intervention with inhaled treprostinil and/or lung transplant evaluation.

PMID:36225536 | PMC:PMC9531548 | DOI:10.1002/pul2.12141

Am J Physiol Lung Cell Mol Physiol. 2022 Oct 12. doi: 10.1152/ajplung.00023.2022. Online ahead of print.

ABSTRACT

Cellular senescence is emerging as a driver of idiopathic pulmonary fibrosis (IPF), a progressive and fatal disease with limited effective therapies. The senescence-associated secretory phenotype (SASP), involving the release of inflammatory cytokines and profibrotic growth factors by senescent cells, is thought to be a product of multiple cell types in IPF, including lung fibroblasts. NF-κB is a master regulator of the SASP, and its activity depends on the phosphorylation of p65/RelA. The purpose of this study was to assess the role of Pim-1 kinase as a driver of NF-κB-induced production of inflammatory cytokines from low-passage IPF fibroblast cultures displaying markers of senescence. Our results demonstrate that Pim-1 kinase phosphorylates p65/RelA, activating NF-κB activity and enhancing IL-6 production, which in turn amplifies expression of PIM1, generating a positive feedback loop. Additionally, targeting Pim-1 kinase with a small molecule inhibitor dramatically inhibited the expression of a broad array of cytokines and chemokines in IPF-derived fibroblasts. Furthermore, we provide evidence that Pim-1 overexpression in low-passage human lung fibroblasts is sufficient to drive premature senescence, in vitro. These findings highlight the therapeutic potential of targeting Pim-1 kinase to reprogram the secretome of senescent fibroblasts and halt IPF progression.

PMID:36223640 | DOI:10.1152/ajplung.00023.2022

Am J Clin Pathol. 2022 Oct 5:aqac118. doi: 10.1093/ajcp/aqac118. Online ahead of print.

ABSTRACT

OBJECTIVES: Oil Red O (ORO) positivity in bronchoalveolar lavage (BAL) fluid macrophages in the setting of e-cigarette, or vaping, product use-associated acute lung injury (EVALI) has been frequently requested by clinicians based on rare reports and subsequent US Centers for Disease Control and Prevention guidelines. The aim of this study was to determine the specificity of ORO staining in BAL specimens with disease states other than EVALI.

METHODS: Consecutive BAL specimens (October-December 2019) were stained with ORO. The lipid-laden macrophage index (LLMI) was calculated for each case.

RESULTS: We studied BAL samples from 50 patients. Indications for BAL were surveillance bronchoscopy for lung transplantation (27/50), suspected infection (12/50), sarcoidosis/suspected sarcoidosis (3/50), nodules or ground-glass opacities (3/50), hemoptysis (2/50), asthma or eosinophilic pneumonia (2/50), and idiopathic pulmonary fibrosis (1/50). ORO staining was seen in BAL fluid macrophages in 45 of 50 cases (focal in 18, moderate in 23, diffuse in 4); LLMI ranged from 0 to 218. Using a threshold of LLMI of 85 or higher as positive, ORO was positive in 7 of 50 (14%) cases (range, 85-218).

CONCLUSIONS: ORO staining in BAL fluid macrophages is not specific for EVALI. Even when an LLMI of 85 or higher is used as a threshold for positivity, ORO positivity occurs in a significant subset of non-vaping-related cases.

PMID:36222561 | DOI:10.1093/ajcp/aqac118

Medicine (Baltimore). 2022 Oct 7;101(40):e30942. doi: 10.1097/MD.0000000000030942.

ABSTRACT

BACKGROUND: To explore the association between Angiotensin Converting Enzyme (ACE) insert(I)/defect(D) gene polymorphism and the susceptibility to idiopathic pulmonary fibrosis (IPF).

METHODS: Searching PubMed, EMbase, CENTRAL, MEDLINE, CBM, China National Knowledge Infrastructure, WanFang Database and VIP Chinese Science database through a computer and collect the literature from China and foreign countries published before January 22, 2022. Screen the literatures and extract data such as first author, year of publication, diagnostic criteria and gene frequency, and draw a funnel chart and perform Begg's Test and Egger's test to evaluate publication bias. The influence analysis was performed for heterogeneous results and at the same time, the trial sequential analysis (TSA) was also conducted to confirm the robustness of the meta-analysis results. Registration number: CRD42021259341.

RESULTS: There were a total of 4 literatures (4 studies conducted in the Chinese Han population), and a total of 292 IPF patients and 351 healthy controls were included in this study. The results showed that in the Chinese Han population, the ACE I/D gene polymorphism was associated with the susceptibility of IPF (D vs I: [odds ratio, OR] = 0.53, 95% confidence interval [95%CI] [0.42, 0.67], P < .00001; DD vs II: [OR] = 0.37, 95%CI [0.24, 0.57], P < .00001; DD vs II + ID:[OR] = 0.30, 95%CI [0.21, 0.43], P < .00001), and the angiotensin II (Ang Ⅱ) level of IPF patients was higher than that of the control group (mean difference [MD] = 14.29, 95%CI [11.20,17.37], P < .00001).The TSA also confirmed that D allele was closely related to the susceptibility of IPF.

CONCLUSION: In the Chinese Han population, the D allele of the ACE I/D gene polymorphism is associated with the susceptibility of IPF.

PMID:36221416 | DOI:10.1097/MD.0000000000030942

Medicine (Baltimore). 2022 Oct 7;101(40):e29981. doi: 10.1097/MD.0000000000029981.

ABSTRACT

BACKGROUND: Fibrotic diseases take a very heavy toll in terms of morbidity and mortality equal to or even greater than that caused by metastatic cancer. This meta-analysis aimed to evaluate the effect of endothelin receptor antagonists on idiopathic pulmonary fibrosis.

METHOD: A systematic search of the clinical trials from the Medline, Google Scholar, Cochrane Library, and PubMed electronic databases was performed. Stata version 12.0 statistical software (Stata Crop LP, College Station, TX) was adopted as statistical software.

RESULT: A total of 5 studies, which included 1500 participants. Our analysis found there is no significant difference between using the endothelin receptor antagonists' group and placebo groups regarding the lung function via estimating both the change of forced vital capacity from baseline and DLco index. Exercise capacity and serious adverse effects are taken into consideration as well; however, there is still no significant change between the 2 groups.

CONCLUSION: This meta-analysis provides insufficient evidence to support that endothelin receptor antagonists' administration provides a benefit among included participants who encounter idiopathic pulmonary fibrosis.

PMID:36221345 | DOI:10.1097/MD.0000000000029981

Respir Res. 2022 Oct 11;23(1):281. doi: 10.1186/s12931-022-02213-4.

ABSTRACT

BACKGROUND: Genes involved in lung development may become dysregulated in adult life and contribute to the pathogenesis of lung diseases. Multiple genes regulate lung development, including Forkhead box protein P1-4 (FoxP1-4).

METHODS: We examined the association between variants in the FoxP1-4 genes and lung function using data from a GWAS that included close to 400,000 individuals and 20 million SNPs.

RESULTS: More than 100 variants in the FoxP1 gene, but none in the FoxP2-4 genes, are associated with lung function. The sentinel variant in the FoxP1 gene associated with FEV1 was rs1499894 (C > T), while the sentinel variant in the FoxP1 gene associated with FVC was rs35480566 (A > G). Those with the T allele instead of the C allele for rs1499894, or the G allele instead of the A allele for rs35480566 had increased FoxP1 mRNA levels in transcriptomic data, higher FEV1 and FVC, and reduced odds of being diagnosed with idiopathic pulmonary fibrosis. Further, knockdown of FoxP1 in lung epithelial cells by RNA interference led to increased mRNA levels for matrix metalloproteinases 1, 2, 3 and pro-inflammatory cytokines IL-6 & IL-8, as well as reduced cell viability after exposure to cigarette smoke-all processes implicated in the pathogenesis of COPD and IPF.

CONCLUSIONS: Our results suggest that the protein encoded by the FoxP1 gene may protect against the development of COPD and IPF. A causal role for FoxP1 in the pathogenesis of COPD and IPF may warrant further investigation, and FoxP1 may be a novel therapeutic target for these lung disorders.

PMID:36221131 | DOI:10.1186/s12931-022-02213-4

Dis Mon. 2022 Oct 8:101484. doi: 10.1016/j.disamonth.2022.101484. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung condition marked by lung scarring that progresses over time and with usual interstitial pneumonia histology (UIP). It is linked to a worsening cough, dyspnea, and a worse quality of life. Around 3 million persons worldwide suffer from IPF, and the prevalence rises sharply with advancing age. The detection of the UIP pattern, generally using high-resolution CT; lung biopsy may be necessary in certain individuals; the diagnostic approach also includes the elimination of other interstitial lung illnesses or overlapping problems. The UIP pattern is mostly bilateral, peripheral, and basal, with clusters of subpleural cystic airspaces and reticular alterations linked to traction bronchiectasis. Although there are still many uncertainties about how to define susceptibility, it is believed that the molecular mechanisms causing IPF reflect an abnormal reparative response to repeated alveolar epithelial damage in an aging genetically sensitive individual. With the availability of two pharmacotherapeutic drugs, pirfenidone and nintedanib, that slow physiological advancement and potentially increase progression-free survival, significant progress has been made in our knowledge of the clinical treatment of IPF. The goal of current research is to develop early biomarkers for IPF that may include circulating variables, demographic information, and imaging data.

PMID:36220705 | DOI:10.1016/j.disamonth.2022.101484