BMC Pulm Med. 2023 Jul 11;23(1):256. doi: 10.1186/s12890-023-02550-0.

ABSTRACT

BACKGROUND: Routinely-collected healthcare data provide a valuable resource for epidemiological research. Validation studies have shown that for most conditions, simple lists of clinical codes can reliably be used for case finding in primary care, however, studies exploring the robustness of this approach are lacking for diseases such as idiopathic pulmonary fibrosis (IPF) which are largely managed in secondary care.

METHOD: Using the UK's Clinical Practice Research Datalink (CPRD) Aurum dataset, which comprises patient-level primary care records linked to national hospital admissions and cause-of-death data, we compared the positive predictive value (PPV) of eight diagnostic algorithms. Algorithms were developed based on the literature and IPF diagnostic guidelines using combinations of clinical codes in primary and secondary care (SNOMED-CT or ICD-10) with/without additional information. The positive predictive value (PPV) was estimated for each algorithm using the death record as the gold standard. Utilization of the reviewed codes across the study period was observed to evaluate any change in coding practices over time.

RESULT: A total of 17,559 individuals had a least one record indicative of IPF in one or more of our three linked datasets between 2008 and 2018. The PPV of case-finding algorithms based on clinical codes alone ranged from 64.4% (95%CI:63.3-65.3) for a "broad" codeset to 74.9% (95%CI:72.8-76.9) for a "narrow" codeset comprising highly-specific codes. Adding confirmatory evidence, such as a CT scan, increased the PPV of our narrow code-based algorithm to 79.2% (95%CI:76.4-81.8) but reduced the sensitivity to under 10%. Adding evidence of hospitalisation to the standalone code-based algorithms also improved PPV, (PPV = 78.4 vs. 64.4%; sensitivity = 53.5% vs. 38.1%). IPF coding practices changed over time, with the increased use of specific IPF codes.

CONCLUSION: High diagnostic validity was achieved by using a restricted set of IPF codes. While adding confirmatory evidence increased diagnostic accuracy, the benefits of this approach need to be weighed against the inevitable loss of sample size and convenience. We would recommend use of an algorithm based on a broader IPF code set coupled with evidence of hospitalisation.

PMID:37434192 | DOI:10.1186/s12890-023-02550-0

Respir Investig. 2023 Jul 8;61(5):579-587. doi: 10.1016/j.resinv.2023.05.006. Online ahead of print.

ABSTRACT

BACKGROUND: Anti-fibrotic therapy has demonstrated efficacy against progressive-fibrosing interstitial lung disease (PF-ILD); therefore, identifying disease behavior before progression has become a priority. As autoimmunity is implicated in the pathogenesis of various ILDs, this study explored circulating biomarkers that could predict the chronic progressive behavior of ILDs.

METHODS: A single-center retrospective cohort study was conducted. Circulating autoantibodies in patients with ILD were screened using microarray analysis to identify candidate biomarkers. An enzyme-linked immunosorbent assay was performed with a larger sample set for the quantification of antibodies. After 2 years of follow-up, ILDs were reclassified as PF or non-PF. The relationship between the participants' autoantibody levels measured at enrolment and final diagnosis of PF-ILD was determined.

RESULTS: In total, 61 healthy participants and 66 patients with ILDs were enrolled. Anti-ubiquitin-conjugating enzyme E2T (UBE2T) antibody was detected as a candidate biomarker. Anti-UBE2T antibody levels were elevated in patients with idiopathic pulmonary fibrosis (IPF). After following up on the study participants for 2 years, anti-UBE2T levels measured at enrolment significantly correlated with the new PF-ILD diagnosis. Immunohistochemical staining of normal lung tissues revealed sparsely located UBE2T in the bronchiole epithelium and macrophages, whereas IPF lung tissues showed robust expression in the epithelial lining of honeycomb structures.

CONCLUSION: To our knowledge, this is the first report to describe an anti-UBE2T antibody, a new biomarker that is significantly elevated in patients with ILD who present future disease progression.

PMID:37429071 | DOI:10.1016/j.resinv.2023.05.006

Iran J Basic Med Sci. 2023;26(8):972-978. doi: 10.22038/IJBMS.2023.68982.15035.

ABSTRACT

OBJECTIVES: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease. Despite the promising anti-fibrotic effect, the toleration of pirfenidone (PFD) by the patients in full dose is low. Combination therapy is a method for enhancing the therapeutic efficiency of PFD and decreasing its dose. Therefore, the present study evaluated the effect of a combination of losartan (LOS) and PFD on oxidative stress parameters and the epithelial-mesenchymal transition (EMT) process induced by bleomycin (BLM) in human lung adenocarcinoma A549 cells.

MATERIALS AND METHODS: The non-toxic concentrations of BLM, LOS, and PFD were assessed by the MTT assay. Malondialdehyde (MDA) and anti-oxidant enzyme activity including catalase (CAT) and superoxide dismutase (SOD) were assessed after co-treatment. Migration and western blot assays were used to evaluate EMT in BLM-exposed A549 after single or combined treatments.

RESULTS: The combination treatment exhibited a remarkable decrease in cellular migration compared with both single and BLM-exposed groups. Furthermore, the combination treatment significantly improved cellular anti-oxidant markers compared with the BLM-treated group. Moreover, combined therapy markedly increased epithelial markers while decreasing mesenchymal markers.

CONCLUSION: This in vitro study revealed that the combination of PFD with LOS might be more protective in pulmonary fibrosis (PF) than single therapy because of its greater efficacy in regulating the EMT process and oxidative stress. The current results might offer a promising therapeutic strategy for the future clinical therapy of lung fibrosis.

PMID:37427320 | PMC:PMC10329237 | DOI:10.22038/IJBMS.2023.68982.15035

J Thorac Dis. 2023 Jun 30;15(6):3054-3068. doi: 10.21037/jtd-22-1522. Epub 2023 May 9.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF), a type of interstitial lung disease (ILD), is a chronic disease with an unknown etiology. The occurrence of lung cancer (LC) is one of the main causes of death in patients with IPF. However, the pathogenesis driving these malignant transformations remains unclear; therefore, this study aimed to identify the shared genes and functional pathways associated with both disease conditions.

METHODS: Data were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. To identify overlapping genes in both diseases, the "limma" package in R software and weighted gene coexpression network analysis (WGCNA) were used. Venn diagrams were used to obtain the shared genes. The diagnostic value of the shared genes was assessed using receiver operating characteristic (ROC) curve analysis. Gene Ontology (GO) term enrichment was performed on the shared genes between lung adenocarcinoma (LUAD) and IPF, and the genes were also functionally enriched using Metascape. A protein-protein interaction (PPI) network was created using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database. Finally, the link between shared genes and common antineoplastic medicines was investigated using the CellMiner database.

RESULTS: The coexpression modules associated with LUAD and IPF were discovered using WGCNA, and 148 genes were found to overlap. In addition, 74 upregulated and 130 downregulated overlapping genes were obtained via differential gene analysis. Functional analysis of the genes revealed that these genes are primarily engaged in extracellular matrix (ECM) pathways. Furthermore, COL1A2, POSTN, COL5A1, CXCL13, CYP24A1, CXCL14, and BMP2 were identified as potential biomarkers in patients with LUAD secondary to IPF showing good diagnostic values.

CONCLUSIONS: ECM-related mechanisms may be the underlying link between LC and IPF. A total of 7 shared genes were identified as potential diagnostic markers and therapeutic targets for LUAD and IPF.

PMID:37426132 | PMC:PMC10323588 | DOI:10.21037/jtd-22-1522

bioRxiv. 2023 Jun 26:2023.06.20.542249. doi: 10.1101/2023.06.20.542249. Preprint.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disorder with limited therapeutic options. Insufficient understanding of driver mutations and poor fidelity of currently available animal models has limited the development of effective therapies. Since GATA1deficient megakaryocytes sustain myelofibrosis, we hypothesized that they may also induce fibrosis in lungs. We discovered that lungs from IPF patients and Gata1 low mice contain numerous GATA1negative immune-poised megakaryocytes that, in mice, have defective RNA-seq profiling and increased TGF-β1, CXCL1 and P-selectin content. With age, Gata1 low mice develop fibrosis in lungs. Development of lung fibrosis in this model is prevented by P-selectin deletion and rescued by P-selectin, TGF-β1 or CXCL1 inhibition. Mechanistically, P-selectin inhibition decreases TGF-β1 and CXCL1 content and increases GATA1positive megakaryocytes while TGF-β1 or CXCL1 inhibition decreased CXCL1 only. In conclusion, Gata1 low mice are the first genetic-driven model for IPF and provide a link between abnormal immune-megakaryocytes and lung fibrosis.

HIGHLIGHTS: Lungs from IPF patients contain many GATA1 negative immune MK Gata1 low mice are the first genetic model with a pathophysiology similar to IPF Gata1 low lungs mice contain defective immune MK with high P-sel, TGF-β and CXCL1 P-sel ablation or P-sel/TGF-β/CXCL1 inhibition rescues fibrosis in Gata1 low lung.

PMID:37425686 | PMC:PMC10327123 | DOI:10.1101/2023.06.20.542249

J Zhejiang Univ Sci B. 2023 Jun 28:1-11. doi: 10.1631/jzus.B2200385. Online ahead of print.

ABSTRACT

Ivermectin is a US Food and Drug Administration (FDA)-approved antiparasitic agent with antiviral and anti-inflammatory properties. Although recent studies reported the possible anti-inflammatory activity of ivermectin in respiratory injuries, its potential therapeutic effect on pulmonary fibrosis (PF) has not been investigated. This study aimed to explore the ability of ivermectin (0.6 mg/kg) to alleviate bleomycin-induced biochemical derangements and histological changes in an experimental PF rat model. This can provide the means to validate the clinical utility of ivermectin as a treatment option for idiopathic PF. The results showed that ivermectin mitigated the bleomycin-evoked pulmonary injury, as manifested by the reduced infiltration of inflammatory cells, as well as decreased the inflammation and fibrosis scores. Intriguingly, ivermectin decreased collagen fiber deposition and suppressed transforming growth factor-‍β1 (TGF-‍β1) and fibronectin protein expression, highlighting its anti-fibrotic activity. This study revealed for the first time that ivermectin can suppress the nucleotide-binding oligomerization domain (NOD)‍-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome, as manifested by the reduced gene expression of NLRP3 and the apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), with a subsequent decline in the interleukin‍-‍1β (IL‍-‍1β) level. In addition, ivermectin inhibited the expression of intracellular nuclear factor-‍κB (NF‍-‍κB) and hypoxia‑inducible factor‑1α (HIF‍-‍1α) proteins along with lowering the oxidative stress and apoptotic markers. Altogether, this study revealed that ivermectin could ameliorate pulmonary inflammation and fibrosis induced by bleomycin. These beneficial effects were mediated, at least partly, via the downregulation of TGF-‍β1 and fibronectin, as well as the suppression of NLRP3 inflammasome through modulating the expression of HIF‑1α and NF-‍κB.

PMID:37423759 | DOI:10.1631/jzus.B2200385

J Biol Chem. 2023 Jul 7:105027. doi: 10.1016/j.jbc.2023.105027. Online ahead of print.

ABSTRACT

Metabolism controls cellular phenotype and fate. In this report, we demonstrate that nicotinamide N-methyltransferase (NNMT), a metabolic enzyme that regulates developmental stem cell transitions and tumor progression, is highly expressed in human idiopathic pulmonary fibrosis (IPF) lungs, and is induced by the pro-fibrotic cytokine, transforming growth factor-β1 (TGF-β1) in lung fibroblasts. NNMT silencing reduces the expression of extracellular matrix proteins, both constitutively and in response to TGF-β1. Furthermore, NNMT controls the phenotypic transition from homeostatic, pro-regenerative lipofibroblasts to pro-fibrotic myofibroblasts. This effect of NNMT is mediated, in part, by downregulation of lipogenic transcription factors, TCF21 and PPARγ, and induction of a less proliferative but more differentiated myofibroblast phenotype. NNMT confers an apoptosis-resistant phenotype to myofibroblasts that is associated with downregulation of pro-apoptotic members of the BCL2 family, including Bim and PUMA. Together, these studies indicate a critical role for NNMT in metabolic reprogramming of fibroblasts to a pro-fibrotic and apoptosis-resistant phenotype and supports the concept that targeting this enzyme may promote regenerative responses in chronic fibrotic disorders such as IPF.

PMID:37423298 | DOI:10.1016/j.jbc.2023.105027

BMC Med Genomics. 2023 Jul 8;16(1):159. doi: 10.1186/s12920-023-01596-7.

ABSTRACT

BACKGROUND: Chronic lung diseases are characterized by impaired lung function. Given that many diseases have shared clinical symptoms and pathogenesis, identifying shared pathogenesis can help the design of preventive and therapeutic strategies. This study aimed to evaluate the proteins and pathways of chronic obstructive pulmonary disease (COPD), asthma, idiopathic pulmonary fibrosis (IPF), and mustard lung disease (MLD).

METHODS AND RESULTS: After collecting the data and determining the gene list of each disease, gene expression changes were examined in comparison to healthy individuals. Protein-protein interaction (PPI) and pathway enrichment analysis were used to evaluate genes and shared pathways of the four diseases. There were 22 shared genes, including ACTB, AHSG, ALB, APO, A1, APO C3, FTH1, GAPDH, GC, GSTP1, HP, HSPB1, IGKC, KRT10, KRT9, LCN1, PSMA2, RBP4, 100A8, S100A9, TF, and UBE2N. The major biological pathways in which these genes are involved are inflammatory pathways. Some of these genes activate different pathways in each disease, leading to the induction or inhibition of inflammation.

CONCLUSION: Identification of the genes and shared pathways of diseases can contribute to identifying pathogenesis pathways and designing preventive and therapeutic strategies.

PMID:37422662 | DOI:10.1186/s12920-023-01596-7

Curr Opin Pulm Med. 2023 Sep 1;29(5):459-464. doi: 10.1097/MCP.0000000000000981. Epub 2023 Jul 7.

ABSTRACT

PURPOSE OF REVIEW: To characterize patterns of disease progression in the designation of progressive pulmonary fibrosis (PPF), including their relative prevalence and subsequent prognostic significance, in patients with fibrotic interstitial lung disease (ILD), including key patient sub-groups.

RECENT FINDINGS: In recent large clinical cohorts, PPF criteria suited to early PPF identification, based on their prevalence and short time to progression, include a relative forced vital capacity (FVC) decline exceeding 10% and various combinations of lower thresholds for FVC decline, symptomatic worsening and serial progression of fibrosis on imaging. Amongst numerous candidate PPF criteria, these progression patterns may have the greatest prognostic significance based on subsequent mortality, although there are conflicting data based on subsequent FVC progression. The prevalence of patterns of progression is similar across major diagnostic sub-groups with the striking exception of patients with underlying inflammatory myopathy.

SUMMARY: Based on prevalence and the prognostic significance of PPF criteria, and the need for early identification of disease progression, recent published data in large clinical cohorts provide support for the use of the INBUILD PPF criteria. The patterns of disease progression used to designate PPF in a recent multinational guideline are mostly not based on data in previous and subsequent real-world cohorts.

PMID:37417940 | DOI:10.1097/MCP.0000000000000981

Medicine (Baltimore). 2023 Jul 7;102(27):e34277. doi: 10.1097/MD.0000000000034277.

ABSTRACT

Cryptogenic organizing pneumonia (COP) is an idiopathic interstitial pneumonia generally requiring steroid therapy, and spontaneous resolution has been reported in patients with mild disease. However, evidence supporting the need for COP treatment is poor. Therefore, we investigated the characteristics of patients with spontaneous resolution. We retrospectively collected data from 40 adult patients who were diagnosed with COP through bronchoscopic examination at Fukujuji Hospital from May 2016 to June 2022. Sixteen patients who improved without steroid therapy (the spontaneous resolution group) and 24 patients who required steroid therapy (the steroid therapy group) were compared. Patients in the spontaneous resolution group showed a lower C-reactive protein (CRP) concentration (median 0.93 mg/dL [interquartile range [IQR] 0.46-1.91] vs median 10.42 mg/dL [4.82-16.7], P < .001), a higher lymphocyte ratio (median 21.7% [18.2-25.2] vs median 13.3% [8.8-19.8], P = .002), and a longer duration from symptom onset to diagnosis of COP (median 51.5 days [24.5-65.3] vs 23.0 days [17.3-31.8], P = .009) than those in the steroid therapy group. Within 2 weeks, all patients in the spontaneous resolution group showed relief of symptoms and alleviated radiographic findings. The area under the receiver operating characteristic (ROC) curve was 0.859 (95% confidence interval [CI]: 0.741-0.978) in CRP. When we arbitrarily determined the cutoff values, including CRP levels of ≤3.79 mg/dL, the sensitivity, specificity, and odds ratio were 73.9%, 93.8%, and 39.8 (95% confidence interval: 4.51-1968.9), respectively. Only 1 patient in the spontaneous resolution group showed recurrence but did not require steroid therapy. Conversely, 4 patients in the steroid therapy group showed recurrence and were treated by an additional course of steroids. The characteristics of COP with spontaneous resolution and factors that determine the patients in whom steroid therapy might be avoided is detailed in this study.

PMID:37417600 | PMC:PMC10328646 | DOI:10.1097/MD.0000000000034277

Ann Afr Med. 2023 Jul-Sep;22(3):246-251. doi: 10.4103/aam.aam_157_21.

ABSTRACT

BACKGROUND: Connective tissue disease associated with interstitial lung disease, or CT-ILD, is a lung condition that affects a large number of patients with a connective tissue disease.

OBJECTIVE: Our aim in this study is to correlation between images of high-resolution computed tomography (HRCT) of different connective tissue diseases associated interstitial lung diseases (CTD-ILDs).

METHODS: We shall be aiming to investigate the feasibility of HRCT imaging and thereby avoid lung biopsy in such patients.

RESULTS: Rheumatoid arthritis predominantly presented with usual interstitial pneumonia (UIP) (47.8%), followed by nonspecific interstitial pneumonia (NSIP) (30.4%). Mixed connective tissue disorder predominantly presented with NSIP and UIP (42.8%), followed by organizing pneumonia (OP) (14.2%). Systemic lupus erythematosus predominantly presented with UIP (38.8%), followed by NSIP (27.7%). Sjogren's syndrome predominantly presented with lymphocytic interstitial pneumonia (40%), followed by UIP (26.6%). Scleroderma predominantly presented with UIP (45.4%), followed by NSIP (36.4%). Sarcoidosis predominantly presented with UIP (75%), followed by NSIP (25%). Dermatomyositis predominantly presented with NSIP (50%), followed by UIP and OP each (25%).

CONCLUSION: Both clinicians and radiologists should be aware of the expected evolution of HRCT changes in a variety of CT-ILDs.

PMID:37417009 | DOI:10.4103/aam.aam_157_21

Nat Rev Drug Discov. 2023 Jul 7. doi: 10.1038/d41573-023-00116-7. Online ahead of print.

NO ABSTRACT

PMID:37419947 | DOI:10.1038/d41573-023-00116-7

Eur Respir J. 2023 Jul 7;62(1):2300881. doi: 10.1183/13993003.00881-2023. Print 2023 Jul.

NO ABSTRACT

PMID:37419523 | DOI:10.1183/13993003.00881-2023

Clin Immunol. 2023 Jul 5:109687. doi: 10.1016/j.clim.2023.109687. Online ahead of print.

ABSTRACT

Pulmonary fibrosis, a serious complication of systemic lupus erythematosus (SLE) and coronavirus disease 2019 (COVID-19), leads to irreversible lung damage. However, the underlying mechanism of this condition remains unclear. In this study, we revealed the landscape of transcriptional changes in lung biopsies from individuals with SLE, COVID-19-induced pulmonary fibrosis, and idiopathic pulmonary fibrosis (IPF) using histopathology and RNA sequencing, respectively. Despite the diverse etiologies of these diseases, lung expression of matrix metalloproteinase genes in these diseases showed similar patterns. Particularly, the differentially expressed genes were significantly enriched in the pathway of neutrophil extracellular trap formation, showing similar enrichment signature between SLE and COVID-19. The abundance of Neutrophil extracellular traps (NETs) was much higher in the lungs of individuals with SLE and COVID-19 compared to those with IPF. In-depth transcriptome analyses revealed that NETs formation pathway promotes epithelial-mesenchymal transition (EMT). Furthermore, stimulation with NETs significantly up-regulated α-SMA, Twist, Snail protein expression, while decreasing the expression of E-cadherin protein in vitro. This indicates that NETosis promotes EMT in lung epithelial cells. Given drugs that are efficacious in degrading damaged NETs or inhibiting NETs production, we identified a few drug targets that were aberrantly expressed in both SLE and COVID-19. Among these targets, the JAK2 inhibitor Tofacitinib could effectively disrupted the process of NETs and reversed NET-induced EMT in lung epithelial cells. These findings support that the NETs/EMT axis, activated by SLE and COVID-19, contributes to the progression of pulmonary fibrosis. Our study also highlights that JAK2 as a potential target for the treatment of fibrosis in these diseases.

PMID:37419296 | DOI:10.1016/j.clim.2023.109687

Int J Biol Sci. 2023 Jun 12;19(10):3042-3056. doi: 10.7150/ijbs.80140. eCollection 2023.

ABSTRACT

Forkhead box protein O3 (FOXO3) has good inhibition ability toward fibroblast activation and extracellular matrix, especially for the treatment of idiopathic pulmonary fibrosis. How FOXO3 regulates pulmonary fibrosis remains unclear. In this study, we reported that FOXO3 had binding sequences with F-spondin 1 (SPON1) promoter, which can activate its transcription and selectively promote the expression of SPON1 circRNA (circSPON1) but not mRNA expression. We further demonstrated that circSPON1 was involved in the extracellular matrix deposition of HFL1. In the cytoplasm, circSPON1 directly interacted with TGF-β1-induced Smad3 and inhibited the activation of fibroblasts by inhibiting nuclear translocation. Moreover, circSPON1 bound to miR-942-5p and miR-520f-3p that interfered with Smad7 mRNA and promoted Smad7 expression. This study revealed the mechanism of FOXO3-regulated circSPON1 in the development of pulmonary fibrosis. Potential therapeutic targets and new insights into the diagnosis and treatment of idiopathic pulmonary fibrosis based on circRNA were also provided.

PMID:37416778 | PMC:PMC10321294 | DOI:10.7150/ijbs.80140

Chemosphere. 2023 Jul 4:139362. doi: 10.1016/j.chemosphere.2023.139362. Online ahead of print.

ABSTRACT

BACKGROUND: The association between long-term air pollution exposure and the development of idiopathic pulmonary fibrosis (IPF) has been established, but the evidence regarding the effect of low levels of air pollution, especially ambient sulfur dioxide (SO2), is limited. Besides, the combined effect and interaction between genetic susceptibility and ambient SO2 on IPF remain uncertain.

METHODS: This study retrieved data from 402,042 participants who were free of IPF at baseline in the UK Biobank. The annual mean concentration of ambient SO2 was estimated for each participant based on their residential addresses using a bilinear interpolation method. Cox proportional hazard models were used to examine the relationship between ambient SO2 and incident IPF. We further generated a polygenic risk score (PRS) for IPF and estimated the combined effects of genetic susceptibility and ambient SO2 on incident IPF.

RESULTS: After a median follow-up of 11.78 years, 2562 cases of IPF were identified. The results indicated that each 1 μg/m3 increase in ambient SO2 was associated with a hazard ratio (HR) (95% confidence interval [CI]) of 1.67 (1.58, 1.76) for incident IPF. The study found statistically significant synergistic additive interaction between genetic susceptibility and ambient SO2. Individuals with high genetic risk and high ambient SO2 exposure had a higher risk of developing IPF (HR = 7.48, 95% CI:5.66, 9.90).

CONCLUSION: The study suggests that long-term exposure to ambient SO2, even at concentrations lower than current air quality guidelines set by the Word Health Organization and European Union, may be an important risk factor for IPF. This risk is more pronounced among people with a high genetic risk. Therefore, these findings emphasize the need to consider the potential health effects of SO2 exposure and the necessity for stricter air quality standards.

PMID:37414299 | DOI:10.1016/j.chemosphere.2023.139362

Am J Respir Cell Mol Biol. 2023 Jul 6. doi: 10.1165/rcmb.2023-0012OC. Online ahead of print.

ABSTRACT

Bleomycin-induced pulmonary fibrosis in mice mimics major hallmarks of idiopathic pulmonary fibrosis, yet in this model it spontaneously resolves over time. We studied molecular mechanisms of fibrosis resolution and lung repair, focusing on transcriptional and proteomic signatures and the effect of aging. Old mice incomplete, yet only delayed lung function recovery 8 weeks after Bleomycin instillation. This shift in structural and functional repair in old Bleomycin-treated mice was reflected in a temporal shift in gene and protein expression. We reveal gene signatures and signaling pathways which underpin the lung repair process. Importantly, the downregulation of WNT, BMP and TGFβ antagonists Frzb, Sfrp1, Dkk2, Grem1, Fst, Fstl1 and Inhba correlated with lung function improvement. Those genes constitute a network with functions in stem cell pathways, wound and pulmonary healing. We suggest that insufficient and delayed downregulation of those antagonists during fibrosis resolution in old mice explains the impaired regenerative outcome. Together, we identified signaling pathway molecules with relevance to lung regeneration that should be tested in depth experimentally as potential therapeutic targets for pulmonary fibrosis.

PMID:37411041 | DOI:10.1165/rcmb.2023-0012OC

Curr Opin Pulm Med. 2023 Jul 7. doi: 10.1097/MCP.0000000000000989. Online ahead of print.

ABSTRACT

PURPOSE OF REVIEW: Genetics contributes substantially to the susceptibility to idiopathic pulmonary fibrosis (IPF). Genetic studies in sporadic and familial disease have identified several IPF-associated variants, mainly in telomere-related and surfactant protein genes.Here, we review the most recent literature on genetics of IPF and discuss how it may contribute to disease pathogenesis.

RECENT FINDINGS: Recent studies implicate genes involved in telomere maintenance, host defence, cell growth, mammalian target of rapamycin signalling, cell-cell adhesion, regulation of TGF-β signalling and spindle assembly as biological processes involved in the pathogenesis of IPF. Both common and rare genetic variants contribute to the overall risk of IPF; however, while common variants (i.e. polymorphisms) account for most of the heritability of sporadic disease, rare variants (i.e. mutations), mainly in telomere-related genes, are the main contributors to the heritability of familial disease. Genetic factors are likely to also influence disease behaviour and prognosis. Finally, recent data suggest that IPF shares genetic associations - and probably some pathogenetic mechanisms - with other fibrotic lung diseases.

SUMMARY: Common and rare genetic variants are associated with susceptibility and prognosis of IPF. However, many of the reported variants fall in noncoding regions of the genome and their relevance to disease pathobiology remains to be elucidated.

PMID:37410458 | DOI:10.1097/MCP.0000000000000989

Cell Signal. 2023 Jul 3:110795. doi: 10.1016/j.cellsig.2023.110795. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease and a severe form of pulmonary fibrosis. Epithelial-mesenchymal transition (EMT) of alveolar epithelial cells is induced in response to epithelial injury, which leads to the accumulation of extracellular matrix in the lung parenchyma and contributes to pulmonary fibrosis. NPAS2 (neuronal PAS domain protein 2) is significantly increased in the lung tissues of IPF patients according to microarray dataset GSE10667 and NPAS2 is downregulated in differentiated human pulmonary type 2 epithelial cells in vitro based on microarray dataset GSE3306 from Gene Expression Omnibus (GEO). In this study, we demonstrated that NPAS2 was increased in bleomycin (BLM)- induced fibrotic lungs in mice. Knockdown of NPAS2 inhibited EMT in primary mouse lung alveolar type 2 epithelial (pmATII) cells and human lung alveolar type 2 epithelial cell line A549 cells under BLM challenge in vitro. Moreover, the silence of NPAS2 alleviated the BLM-induced pulmonary fibrosis in a murine model. Mechanistically, NPAS2 promotes EMT through positively regulating hairy and enhancer of split 1 (HES1) expression. In this study, we present novel findings that have not been previously reported, emphasizing that p53 transcriptionally activates NPAS2 in ATII cells and overexpression of NPAS2 weakens the effects of TP53 knockdown on EMT of pmATII and A549 cells. Our results suggest NPAS2 is a novel target gene of p53 in regulating BLM-mediated EMT in ATII cells and pulmonary fibrosis.

PMID:37406788 | DOI:10.1016/j.cellsig.2023.110795

Respirology. 2023 Jul 5. doi: 10.1111/resp.14550. Online ahead of print.

NO ABSTRACT

PMID:37408091 | DOI:10.1111/resp.14550