Immunol Allergy Clin North Am. 2023 May;43(2):209-228. doi: 10.1016/j.iac.2023.01.010. Epub 2023 Mar 3.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF), a common interstitial lung disease (ILD), is a chronic, progressive fibrosing interstitial pneumonia, with an unknown cause. IPF has been linked to several genetic and environmental risk factors. Disease progression is common and associated with worse outcomes. Management often encompasses pharmacotherapy, supportive interventions, addressing comorbidities when present, and treating hypoxia with ambulatory O2. Consideration for antifibrotic therapy and lung transplantation evaluation should occur early. Patients with ILD other than IPF, and who have radiological evidence of pulmonary fibrosis, may have progressive pulmonary fibrosis.

PMID:37055085 | DOI:10.1016/j.iac.2023.01.010

Arthritis Care Res (Hoboken). 2023 Apr 13. doi: 10.1002/acr.25133. Online ahead of print.

ABSTRACT

Interstitial lung disease(ILD) and pulmonary hypertension(PH) caused by connective tissue disease(CTD) are one of the main causes of morbidity and mortality in patients. Although International Heart and Lung Transplant Society (ISHLT) suggested that ILD and PH related to CTD are rare indications for lung transplantation(LTx) in 2006, many LTx centers are concerned that the multi-system involvement of CTD will affect the survival outcome after lung transplantation, and CTD is regarded as a relative contraindication for LTx. However，long-term and short-term survival after LTx in CTD patients is similar to that in common indications for LTx such as idiopathic pulmonary fibrosis(IPF)，and no higher complications after transplantation in many lung transplant centers. This suggests that LTx may be beneficial for CTD patients who progress to end-stage lung disease, and CTD patients should not be considered a contraindication to LTx. In the future, more prospective studies are needed to analyze the risk factors of LTx in CTD patients to improve survival and reduce the risk of complications. This narrative review summarizes the selection and evaluation of candidates for CTD before LTx, and describes the clinical outcome of CTD after LTx in large-capacity lung transplantation center, the purpose is to help rheumatologists decide when to refer patients with CTD lung involvement to an LTx center and the conditions to consider before transplantation, and to provide confidence to lung transplant experts. This article is protected by copyright. All rights reserved.

PMID:37052523 | DOI:10.1002/acr.25133

Front Immunol. 2023 Mar 27;14:1119139. doi: 10.3389/fimmu.2023.1119139. eCollection 2023.

ABSTRACT

BACKGROUND: IPF is an undetermined, progressive lung disease. Necroptosis is a type of programmed apoptosis, which involved in the pathogenesis of lung diseases like COPD and ARDS. However, necroptosis in IPF have not been adequately studied. This study aimed to investigate the necroptosis in IPF and the relationship between necroptosis and immune infiltration, to construct a prognostic prediction model of IPF based on necroptosis-related genes.

METHODS: GSE110147 was downloaded from the GEO database and utilized to analyze the expression of necroptosis-related differentially expressed genes (NRDEGs). Then NRDEGs were used to construct protein-protein interaction (PPI) networks in the STRING database, and Cytoscape software was used to identify and visualize hub genes. Necroptosis-related prognosticgenes were explored in GSE70866, and a prognostic prediction model was constructed. The ImmuCellAI algorithm was utilized to analyze the landscape of immune infiltration in GSE110147. The single-cell RNA sequencing dataset GSE122960 was used to explore the association between necroptosis and type II alveolar epithelial cells (AT II) in IPF. The GSE213001 and GSE93606 were used for external validation. The expression of prognostic genes was quantified using RT-qPCRin the IPF A549 cell model, and was further verified by western blotting in the bleomycin-induced pulmonary fibrosis mouse model.

RESULTS: It was observed that necroptosis-related signaling pathways were abundantly enriched in IPF. 29 NRDEGs were screened, of which 12 showed consistent expression trends in GSE213001. Spearman correlation analysis showed that the expression of NRDEGs was positively correlated with the infiltration of proinflammatory immune cells, and negatively correlated with the infiltration of anti-inflammatory immune cells. NRDEGs, including MLKL, were highly expressed in AT II of fibrotic lung tissue. A necroptosis-related prediction model was constructed based on 4 NRDEGsby the cox stepwise regression. In the validation dataset GSE93606, the prognostic prediction model showed good applicability. The verification results of RT-qPCR and western blotting showed the reliability of most of the conclusions.

CONCLUSIONS: This study revealed that necroptosis existed in IPF and might occur in AT II. Necroptosis was associated with immune infiltration, suggesting that necroptosis of AT II might involve in IPF by activating immune infiltration and immune response.

PMID:37051233 | PMC:PMC10083386 | DOI:10.3389/fimmu.2023.1119139

Int J Gen Med. 2023 Apr 6;16:1227-1236. doi: 10.2147/IJGM.S400060. eCollection 2023.

ABSTRACT

PURPOSE: Spontaneous pneumomediastinum, supposedly attributed to air leakage from the respiratory tract, is a common complication of interstitial lung disease often resulting in mediastinal widening. However, several cases of pneumomediastinum without mediastinal widening have been observed. This study aimed to investigate the cause of pneumomediastinum in patients without mediastinal widening.

PATIENTS AND METHODS: This study included 41 patients diagnosed with pneumomediastinum using computed tomography (CT) between July 2011 and September 2021 at Yokohama Minamikyosai Hospital; patients had undergone previous CT showing no gas density. Based on a comparison with previous CT images, the patients were classified into two groups: without mediastinal widening and with mediastinal widening.

RESULTS: Of the 41 patients, 13 and 28 had pneumomediastinum without and with mediastinal widening, respectively. There were no significant differences in the sex, age, body mass index, or pneumomediastinum distribution between the groups. However, the rate of weight loss per month was significantly greater in the group without mediastinal widening than in that with mediastinal widening. No significant differences were observed in the respiratory function test results between the two groups; that said, 10 of the 13 patients without mediastinal widening had restrictive disorders. Pulmonary disease in this group included idiopathic pulmonary fibrosis (n = 6), interstitial lung disease with collagen disease (n = 4), and other disease (n = 1). Pneumomediastinum occurred during periods of weight loss in all patients without widening, excluding two patients without data.

CONCLUSION: Pneumomediastinum without mediastinal widening occurs during rapid weight loss and is often associated with restrictive lung disorders. The negative pressure attributed to the decreased plasticity of the lungs, which complements the space where the mediastinal fat has disappeared, is presumably the cause of pneumomediastinum. This pathophysiology is different from that of conventional pneumomediastinum attributed to increased intrapleural space pressure; thus, we propose to name the abovementioned pathophysiology "negative pressure pneumomediastinum".

PMID:37051133 | PMC:PMC10084867 | DOI:10.2147/IJGM.S400060

Molecules. 2023 Apr 1;28(7):3157. doi: 10.3390/molecules28073157.

ABSTRACT

The balance between anabolism and catabolism is disrupted with aging, with the rate of anabolism being faster than that of catabolism. Therefore, mTOR, whose major function is to enhance anabolism and inhibit catabolism, has become a potential target of inhibition for anti-aging therapy. Interestingly, it was found that the downregulation of the mTOR signaling pathway had a lifespan-extending effect resembling calorie restriction. In addition, the mTOR signaling pathway promotes cell proliferation and has been regarded as a potential anti-cancer target. Rapamycin and rapalogs, such as everolimus, have proven to be effective in preventing certain tumor growth. Here, we reviewed the basic knowledge of mTOR signaling, including both mTORC1 and mTORC2. Then, for anti-aging, we cited a lot of evidence to discuss the role of targeting mTOR and its anti-aging mechanism. For cancer therapy, we also discussed the role of mTOR signaling in different types of cancers, including idiopathic pulmonary fibrosis, tumor immunity, etc. In short, we discussed the research progress and both the advantages and disadvantages of targeting mTOR in anti-aging and anti-cancer therapy. Hopefully, this review may promote more ideas to be generated for developing inhibitors of mTOR signaling to fight cancer and extend lifespan.

PMID:37049920 | DOI:10.3390/molecules28073157

Cells. 2023 Mar 30;12(7):1044. doi: 10.3390/cells12071044.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease with a very poor prognosis as it has a 2.5 to 5 years mean survival after proper diagnosis. Even nintedanib and pirfenidone cannot halt the progression, though they slow the progression of IPF. Hence, there is a need to understand the novel pathophysiology. Phospholipase A2 (PLA2) could be the ideal candidate to study in IPF, as they have a role in both inflammation and fibrosis. In the present study, we have shown the expression profile of various secretory Phospholipase A2 (PLA2) isoforms by analyzing publicly available transcriptome data of single cells from the lungs of healthy individuals and IPF patients. Among 11 members of sPLA2, PLA2G2A is found to be increased in the fibroblasts and mesothelial cells while PLA2G5 is found to be increased in the fibroblasts of IPF patients. We identified a subset of fibroblasts expressing high PLA2G2A with moderate expression of PLA2G5 and which are specific to IPF only; we named it as PLA2G2A+ IPF fibroblast. Pathway analysis revealed that these PLA2G2A+ IPF fibroblast have upregulation of both inflammatory and fibrosis-related pathways like the TGF-β signaling pathway, IL-17 signaling, the arachidonic acid metabolism pathway and ECM-receptor interaction. In addition to this, we found elevated levels of sPLA2-IIA in plasma samples of IPF patients in our cohort. PLA2G3, PLA2G10 and PLA2G12B are found in to be increased in certain epithelial cells of IPF patients. Thus, these findings indicate that these five isoforms have a disease-dominant role along with innate immune roles as these isoforms are found predominantly in structural cells of IPF patients. Further, we have targeted sPLA2 in mice model of bleomycin-induced lung fibrosis by pBPB, a known sPLA2 inhibitor. pBPB treatment attenuated lung fibrosis induced by bleomycin along with a reduction in TGF-β and deposition of extracellular matrix in lung. Thus, these findings indicate that these sPLA2 isoforms especially PLA2G2A may serve as a therapeutic target in lung fibrosis.

PMID:37048117 | DOI:10.3390/cells12071044

Cells. 2023 Mar 27;12(7):1020. doi: 10.3390/cells12071020.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic and fatal disease characterized by progressive and irreversible lung scarring associated with persistent activation of fibroblasts. Epigenetics could integrate diverse microenvironmental signals, such as stiffness, to direct persistent fibroblast activation. Histone modifications by deacetylases (HDAC) may play an essential role in the gene expression changes involved in the pathological remodeling of the lung. Particularly, HDAC3 is crucial for maintaining chromatin and regulating gene expression, but little is known about its role in IPF. In the study, control and IPF-derived fibroblasts were used to determine the influence of HDAC3 on chromatin remodeling and gene expression associated with IPF signature. Additionally, the cells were grown on hydrogels to mimic the stiffness of a fibrotic lung. Our results showed a decreased HDAC3 in the nucleus of IPF fibroblasts, which correlates with changes in nucleus size and heterochromatin loss. The inhibition of HDAC3 with a pharmacological inhibitor causes hyperacetylation of H3K9 and provokes an increased expression of Col1A1, ACTA2, and p21. Comparable results were found in hydrogels, where matrix stiffness promotes the loss of nuclear HDAC3 and increases the profibrotic signature. Finally, latrunculin b was used to confirm that changes by stiffness depend on the mechanotransduction signals. Together, these results suggest that HDAC3 could be a link between epigenetic mechanisms and the fibrotic microenvironment.

PMID:37048093 | DOI:10.3390/cells12071020

Int J Mol Sci. 2023 Apr 3;24(7):6695. doi: 10.3390/ijms24076695.

ABSTRACT

Idiopathic pulmonary fibrosis is a progressive and fatal disease with a poor prognosis. Matrix metalloproteinase-2 is involved in the pathogenesis of organ fibrosis. The role of matrix metalloproteinase-2 in lung fibrosis is unclear. This study evaluated whether overexpression of matrix metalloproteinase-2 affects the development of pulmonary fibrosis. Lung fibrosis was induced by bleomycin in wild-type mice and transgenic mice overexpressing human matrix metalloproteinase-2. Mice expressing human matrix metalloproteinase-2 showed significantly decreased infiltration of inflammatory cells and inflammatory and fibrotic cytokines in the lungs compared to wild-type mice after induction of lung injury and fibrosis with bleomycin. The computed tomography score, Ashcroft score of fibrosis, and lung collagen deposition were significantly reduced in human matrix metalloproteinase transgenic mice compared to wild-type mice. The expression of anti-apoptotic genes was significantly increased, while caspase-3 activity was significantly reduced in the lungs of matrix metalloproteinase-2 transgenic mice compared to wild-type mice. Active matrix metalloproteinase-2 significantly decreased bleomycin-induced apoptosis in alveolar epithelial cells. Matrix metalloproteinase-2 appears to protect against pulmonary fibrosis by inhibiting apoptosis of lung epithelial cells.

PMID:37047672 | DOI:10.3390/ijms24076695

Int J Mol Sci. 2023 Mar 24;24(7):6172. doi: 10.3390/ijms24076172.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease characterized by lung inflammation and excessive deposition of extracellular matrix components. Transforming growth factor-β1 (TGF-β1) induced epithelial-mesenchymal transformation of type 2 lung epithelial cells leads to excessive extracellular matrix deposition, which plays an important role in fibrosis. Our objective was to evaluate the effects of 3-cyclopropylmethoxy-4-(difluoromethoxy) benzoic acid (DGM) on pulmonary fibrosis and aimed to determine whether EMT plays a key role in the pathogenesis of pulmonary fibrosis and whether EMT can be used as a therapeutic target for DGM therapy to reduce IPF. Firstly, stimulation of in vitro cultured A549 cells to construct EMTs with TGF-β1. DGM treatment inhibited the expression of proteins such as α-SMA, vimentin, and collagen Ⅰ and increased the expression of E-cadherin. Accordingly, Smad2/3 phosphorylation levels were significantly reduced by DGM treatment. Secondly, models of tracheal instillation of bleomycin and DGM were used to treat rats to demonstrate their therapeutic effects, such as improving lung function, reducing lung inflammation and fibrosis, reducing collagen deposition, and reducing the expression of E-cadherin. In conclusion, DGM attenuates TGF-β1-induced EMT in A549 cells and bleomycin-induced pulmonary fibrosis in rats.

PMID:37047142 | DOI:10.3390/ijms24076172

AJR Am J Roentgenol. 2023 Apr 12. doi: 10.2214/AJR.23.29119. Online ahead of print.

ABSTRACT

Pulmonary fibrosis is recognized to occur in association with a wide and increasing array of conditions, and presents with a spectrum of chest CT appearances. Idiopathic pulmonary fibrosis (IPF), corresponding histologically with usual interstitial pneumonia and representing the most common idiopathic interstitial pneumonia, is a chronic progressive fibrotic interstitial lung disease (ILD) of unknown cause. Progressive pulmonary fibrosis (PPF) describes the radiologic development of pulmonary fibrosis in patients with ILD of a known or unknown cause other than IPF. The recognition of PPF impacts management of patients with ILD, for example guiding initiation of antifibrotic therapy. Interstitial lung abnormalities (ILAs) represent an incidental CT finding in patients without suspected ILD and may represent an early intervenable form of pulmonary fibrosis. Traction bronchiectasis and/or bronchiolectasis, when detected in the setting of chronic fibrosis, is generally considered evidence of irreversible disease, and progression predicts worse mortality. Awareness is increasing of the relation between pulmonary fibrosis and connective tissue diseases, particularly rheumatoid arthritis. This review provides an update on imaging of pulmonary fibrosis, with attention to recent advances in disease understanding with relevance to radiologic practice. The essential role of a multidisciplinary approach to clinical and radiologic data is highlighted.

PMID:37095673 | DOI:10.2214/AJR.23.29119

Case Rep Transplant. 2023 Apr 12;2023:1737309. doi: 10.1155/2023/1737309. eCollection 2023.

ABSTRACT

Interstitial lung disease is characterised by a combination of cellular proliferation, inflammation of the interstitium and fibrosis within the alveolar wall. A 58-year-old man was referred for lung transplantation after developing worsening dyspnoea and progressive hypoxaemic respiratory failure from idiopathic pulmonary fibrosis. Three years later, he developed desquamative interstitial pneumonia in his transplanted lungs, and despite augmentation of immune suppression, he had a progressive decline in his lung function and exercise capacity. Interestingly, in our case, the histopathology obtained post transplant strongly goes against the recurrence of usual interstitial pneumonia/idiopathic pulmonary fibrosis; rather, two separate interstitial disease processes have been identified.

PMID:37090840 | PMC:PMC10115523 | DOI:10.1155/2023/1737309

Sci Rep. 2023 Apr 12;13(1):5941. doi: 10.1038/s41598-023-32452-4.

ABSTRACT

5-methyladenosine (m5C) modification regulates gene expression and biological functions in oncologic areas. However, the effect of m5C modification in chronic hypersensitivity pneumonitis (CHP) and idiopathic pulmonary fibrosis (IPF) remains unknown. Expression data for 12 significant m5C regulators were obtained from the interstitial lung disease dataset. Five candidate m5C regulators, namely tet methylcytosine dioxygenase 2, NOP2/Sun RNA methyltransferase 5, Y-box binding protein 1, tRNA aspartic acid methyltransferase 1, and NOP2/Sun RNA methyltransferase 3 were screened using random forest and nomogram models to predict risks of pulmonary fibrosis. Next, we applied the consensus clustering method to stratify the samples with different m5C patterns into two groups (cluster A and B). Finally, we calculated immune cell infiltration scores via single-sample gene set enrichment analysis, then compared immune cell infiltration, related functions as well as the expression of programmed cell death 1 (PD-1, PDCD1) and programmed death protein ligand-1 (PD-L1, CD274) between the two clusters. Principal component analysis of m5C-related scores across the 288 samples revealed that cluster A had higher immune-related expression than B. Notably, T helper cell (Th) 2 type cytokines and Th1 signatures were more abundant in clusters A and B, respectively. Our results suggest that m5C is associated with and plays a crucial role in development of pulmonary fibrosis. These m5C patterns could be potential biomarkers for identification of CHP and IPF, and guide future development of immunotherapy or other new drugs strategies for pulmonary fibrosis.

PMID:37045913 | DOI:10.1038/s41598-023-32452-4

Sci Rep. 2023 Apr 12;13(1):5986. doi: 10.1038/s41598-023-32915-8.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a severe and progressive chronic fibrosing interstitial lung disease with causes that have remained unclear to date. Development of effective treatments will require elucidation of the detailed pathogenetic mechanisms of IPF at both the molecular and cellular levels. With a biomedical corpus that includes IPF-related entities and events, text-mining systems can efficiently extract such mechanism-related information from huge amounts of literature on the disease. A novel corpus consisting of 150 abstracts with 9297 entities intended for training a text-mining system was constructed to clarify IPF-related pathogenetic mechanisms. For this corpus, entity information was annotated, as were relation and event information. To construct IPF-related networks, we also conducted entity normalization with IDs assigned to entities. Thereby, we extracted the same entities, which are expressed differently. Moreover, IPF-related events have been defined in this corpus, in contrast to existing corpora. This corpus will be useful to extract IPF-related information from scientific texts. Because many entities and events are related to lung diseases, this freely available corpus can also be used to extract information related to other lung diseases such as lung cancer and interstitial pneumonia caused by COVID-19.

PMID:37045907 | DOI:10.1038/s41598-023-32915-8

BMC Pulm Med. 2023 Apr 11;23(1):114. doi: 10.1186/s12890-023-02378-8.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis is thought to result from aberrant post-injury activation of epithelial cells leading to fibroblast proliferation and activation. A number of genetic aetiologies have been implicated in this disease process, including, among others, the short telomere syndromes. Short telomere syndromes follow an autosomal dominant pattern of inheritance resulting in shortened telomere length, which consequently leads to accelerated cell death. Organs with rapid cell turnover are most affected.

CASE PRESENTATION: We describe a case of a 53-year-old man with a chief complaint of cough and dyspnea on exertion. His presentation was otherwise significant for features of accelerated aging, including a history of osteoporosis and early greying, and a family history of pulmonary fibrosis in his father. Pulmonary function testing revealed a restrictive pattern with severely reduced diffusion capacity and high resolution CT of the chest showed diffuse lung disease with mild fibrosis, in pattern suggesting an alternative diagnosis to IPF. Biopsy of the lung was in keeping with chronic fibrosing interstitial pneumonia. Imaging of the abdomen showed splenomegaly, hepatic cirrhosis and portal hypertension. Transthoracic contrast echocardiogram showed intrapulmonary shunting consistent with hepatopulmonary syndrome. Given the constellation of early aging, idiopathic pulmonary fibrosis, cryptogenic cirrhosis and a family history of pulmonary fibrosis in this patient, the Short Telomere Syndrome was suspected. Peripheral blood was sent for Flow-cytometry FISH, which demonstrated granulocyte telomere length below the 10th percentile for the patient's age, consistent with a diagnosis of Short Telomere Syndrome in this clinical context. Targeted genetic testing of mutations known to be associated with short telomere was negative though it was acknowledged that the full spectrum of disease-causing mutations remains unknown. Given the extensive fibrosis on biopsy and his progressive hypoxemia he was treated with mycophenolate and prednisone. Ultimately, he developed progressive respiratory failure and underwent double lung and concurrent liver transplant 18 months after the initial diagnosis was made.

CONCLUSIONS: Short Telomere Syndrome is a rare cause of end stage organ disease and testing lacks sensitivity making diagnosis challenging. Organ transplant is still the mainstay of treatment. Nevertheless, disease identification is important because of implications for family member screening and the possibility of future treatment options.

PMID:37041499 | DOI:10.1186/s12890-023-02378-8

Am J Physiol Lung Cell Mol Physiol. 2023 Apr 11. doi: 10.1152/ajplung.00439.2022. Online ahead of print.

ABSTRACT

Radiation-induced lung injury is a consequence of therapeutic irradiation (TR) for thoracic cancers. Studies report that up to 80% of patients who undergo TR will have CT-detectable interstitial lung abnormalities, and strategies to limit the risk of RILI may make radiotherapy less effective at treating cancer. Our lab and others have reported that lung tissue from patients with idiopathic pulmonary fibrosis exhibit metabolic defects including increased glycolysis and lactate production. Here, we hypothesized that patients with radiation-induced lung damage will exhibit distinct changes in lung metabolism that may be associated with incidence of fibrosis. Using liquid chromatography/tandem mass spectrometry to identify metabolic compounds, we analyzed exhaled breath condensate (EBC) in subjects with CT-confirmed lung lesions after TR for lung cancer, compared to healthy subjects, smokers, and cancer patients who had not yet received TR. The lung metabolomic profile of the fibrosis case group was significantly different from the 3 control groups. Along with increased levels of lactate, pathway enrichment analysis revealed that EBC from the case patients exhibited upregulations of the fatty acid oxidation and glutamate pathways. As radiation induces aerobic glycolysis and production of lactate which drives myofibroblast differentiation, our results support the hypothesis that preferential conversion of pyruvate to lactate deprives the tricarboxylic acid cycle of a key input, requiring compensatory upregulation of alternative energy inputs to meet the metabolic demands of chronic wound repair. Utilizing an 'omics' approach to probe lung disease in a non-invasive manner could inform future mechanistic investigations and development of novel therapeutic targets.

PMID:37039378 | DOI:10.1152/ajplung.00439.2022

Adv Sci (Weinh). 2023 Apr 10:e2207454. doi: 10.1002/advs.202207454. Online ahead of print.

ABSTRACT

Pulmonary fibrosis (PF) is a heterogeneous disease with a poor prognosis. Therefore, identifying additional therapeutic modalities is required to improve outcome. However, the lack of biomarkers of disease progression hampers the preclinical to clinical translational process. Here, this work assesses and identifies progressive alterations in pulmonary function, transcriptomics, and metabolomics in the mouse lung at 7, 14, 21, and 28 days after a single dose of oropharyngeal bleomycin. By integrating multi-omics data, this work identifies two central gene subnetworks associated with multiple critical pathological changes in transcriptomics and metabolomics as well as pulmonary function. This work presents a multi-omics-based framework to establish a translational link between the bleomycin-induced PF model in mice and human idiopathic pulmonary fibrosis to identify druggable targets and test therapeutic candidates. This work also indicates peripheral cannabinoid receptor 1 (CB1 R) antagonism as a rational therapeutic target for clinical translation in PF. Mouse Lung Fibrosis Atlas can be accessed freely at https://niaaa.nih.gov/mouselungfibrosisatlas.

PMID:37038090 | DOI:10.1002/advs.202207454

Front Genet. 2023 Mar 24;14:1157258. doi: 10.3389/fgene.2023.1157258. eCollection 2023.

ABSTRACT

Background: Idiopathic pulmonary fibrosis (IPF), a chronic, progressive lung disease characterized by interstitial remodeling and tissue destruction, affects people worldwide and places a great burden on society. Cellular senescence is thought to be involved in the mechanisms and development of IPF. The aim of this study was to predictively investigate subtypes of IPF according to cellular senescence-related genes and their correlation with the outcome of patients with IPF, providing possible treatment and management options for disease control. Methods: Gene expression profiles and follow-up data were obtained from the GEO database. Senescence-related genes were obtained from the CSGene database and analyzed their correlation with the outcome of IPF. A consensus cluster was constructed to classify the samples based on correlated genes. The GSVA and WGCNA packages in R were used to calculate the immune-related enriched fractions and construct gene expression modules, respectively. Metascape and the clusterProfiler package in R were used to enrich gene functions. The ConnectivityMap was used to probe suitable drugs for potential treatment. Results: A total of 99 cellular senescence-related genes were associated with IPF prognosis. Patients with IPF were divided into two subtypes with significant prognostic differences. Subtype S2 was characterized by enhanced fibrotic progression and infection, leading to acute exacerbation of IPF and poor prognosis. Finally, five cellular senescence-related genes, TYMS, HJURP, UBE2C, BIRC5, and KIF2C, were identified as potential biomarkers in poor prognostic patients with IPF. Conclusion: The study findings indicate that cellular senescence-related genes can be used to distinguish the prognosis of patients with IPF. Among them, five genes can be used as candidate biomarkers to predict patients with a poor prognostic subtype for which anti-fibrosis and anti-infection treatments could be suitable.

PMID:37035748 | PMC:PMC10079953 | DOI:10.3389/fgene.2023.1157258

Adv Redox Res. 2023 Apr;7:100065. doi: 10.1016/j.arres.2023.100065. Epub 2023 Feb 18.

ABSTRACT

Cadmium (Cd) is a toxic environmental metal that interacts with selenium (Se) and contributes to many lung diseases. Humans have widespread exposures to Cd through diet and cigarette smoking, and studies in rodent models show that Se can protect against Cd toxicities. We sought to identify whether an antagonistic relationship existed between Se and Cd burdens and determine whether this relationship may associate with metabolic variation within human lungs. We performed metabolomics of 31 human lungs, including 25 with end-stage lung disease due to idiopathic pulmonary fibrosis, cystic fibrosis, chronic obstructive lung disease (COPD)/emphysema and other causes, and 6 non-diseased lungs. Results showed pathway associations with Cd including amino acid, lipid and energy-related pathways. Metabolic pathways varying with Se had considerable overlap with these pathways. Hierarchical cluster analysis (HCA) of individuals according to metabolites associated with Cd showed partial separation of disease types, with COPD/emphysema in the cluster with highest Cd, and non-diseased lungs in the cluster with the lowest Cd. When compared to HCA of metabolites associated with Se, the results showed that the cluster containing COPD/emphysema had the lowest Se, and the non-diseased lungs had the highest Se. A greater number of pathway associations occurred for Cd to Se ratio than either Cd or Se alone, indicating that metabolic patterns were more dependent on Cd to Se ratio than on either alone. Network analysis of interactions of Cd and Se showed network centrality was associated with pathways linked to polyunsaturated fatty acids involved in inflammatory signaling. Overall, the data show that metabolic pathway responses in human lung vary with Cd and Se in a pattern suggesting that Se is antagonistic to Cd toxicity in humans.

PMID:37034445 | PMC:PMC10078579 | DOI:10.1016/j.arres.2023.100065

Respir Res. 2023 Apr 10;24(1):107. doi: 10.1186/s12931-023-02411-8.

NO ABSTRACT

PMID:37032327 | DOI:10.1186/s12931-023-02411-8

Sci Rep. 2023 Apr 8;13(1):5774. doi: 10.1038/s41598-023-32843-7.

ABSTRACT

Patients with idiopathic pulmonary fibrosis (IPF) often experience weight loss during the follow-up period. However, the prevalence and clinical impact of weight loss in these patients still need to be elucidated. This retrospective single-center study reviewed 134 consecutive patients diagnosed with IPF. Weight loss of 5% or more over 1 year was defined as significant weight loss. Clinical data of patients were compared according to the significant weight loss. We analyzed whether the clinical impact of significant weight loss differed regarding the pirfenidone dose. The median follow-up period was 22.1 months. The mean age of patients was 67.3 years, and 92.5% were men. Of the 134 patients, 42 (31.3%) showed significant weight loss. Multivariate cox regression analysis revealed that significant weight loss was independently associated with mortality (hazard ratio [HR]; 2.670; 95% confidence interval [CI] 1.099-6.484; p = 0.030) after adjusting for lung function and other significant risk factors (6-min walk test distance: HR, 0.993; 95% CI 0.987-0.998; p = 0.005). The median survival of patients with significant weight loss (n = 22) was relevantly shorter than that of those without significant weight loss (n = 43) in the reduced dose pirfenidone group (28.2 ± 3.3 vs. 43.3 ± 3.2 months, p = 0.013). Compared with patients without significant weight loss (n = 38), patients with significant weight loss (n = 15) also showed a marginally-significant shorter survival in the full-dose pirfenidone group (28.9 ± 3.1 vs. 39.8 ± 2.6 months, p = 0.085). Significant weight loss is a prognostic factor in patients with IPF regardless of pirfenidone dose. Vigilant monitoring might be necessary to detect weight loss during the clinical course in these patients.

PMID:37031256 | DOI:10.1038/s41598-023-32843-7