Bioinformatics analysis of hypoxia associated genes and inflammatory cytokine profiling in COPD-PH.

Pulmonary hypertension (PH) in chronic obstructive pulmonary disease (COPD) is associated with worse clinical outcomes and decreased survival rates. In absence of disease specific diagnostic/therapeutic targets and unclear pathophysiology, there is an urgent need for the identification of potential genetic/molecular markers and disease associated pathways. The present study aims to use a bioinformatics approach to identify and validate hypoxia-associated gene signatures in COPD-PH patients. Additionally, hypoxia-related inflammatory profile is also explored in these patients. Microarray dataset obtained from the Gene Expression Omnibus repository was used to identify differentially expressed genes (DEGs) in a hypoxic PH mice model. The top three hub genes identified were further validated in COPD-PH patients, with chemokine (C-X-C motif) ligand 9 (CXCL9) and CXCL12 showing significant changes in comparison to healthy controls. Furthermore, multiplexed analysis of 10 inflammatory cytokines, tumor necrosis factor alpha (TNF-α), transforming growth factor ß (TGF-ß), interleukin 1-beta (IL-1ß), IL-4, IL-5, IL-6, IL-13, IL-17, IL-18 and IL-21 was also performed. These markers showed significant changes in COPD-PH patients as compared to controls. They also exhibited the ability to differentially diagnose COPD-PH patients in comparison to COPD. Additionally, IL-6 and IL-17 showed significant positive correlation with systolic pulmonary artery pressure (sPAP). This study is the first report to assess the levels of CXCL9 and CXCL12 in COPD-PH patients and also explores their link with the inflammatory profile of these patients. Our findings could be extended to better understand the underlying disease mechanism and possibly used for tailoring therapies exclusive for the disease.

Discovery of novel metabolic signatures for early identification of women at risk of developing gestational hypertension.

INTRODUCTION: Gestational hypertension (GH) is defined as the presence of systolic blood pressure (BP) ≥ 140 mm Hg and/or diastolic BP ≥ 90 mm Hg, measured at least 4 h apart after 20 weeks of gestation. Early identification of women at high-risk of developing GH could contribute significantly towards improved maternal and fetal outcomes. OBJECTIVES: To determine early metabolic biomarkers in women with GH as compared with normotensive women. METHODS: Serum samples were collected from subjects during three stages of their pregnancy: 8-12 weeks, 18-20 weeks and after 28 weeks (< 36 weeks) of gestation and studied using nuclear magnetic resonance (NMR) metabolomics approach. Multivariate and univariate analyses were performed to determine the significantly altered metabolites in GH women. RESULTS: A total of 10 metabolites, including isoleucine, glutamine, lysine, proline, histidine, phenylalanine, alanine, carnitine, N-acetyl glycoprotein and lactic acid were observed to be significantly downregulated during all pregnancy stages in women with GH as compared with controls. Furthermore, expression of 5 metabolites in the first trimester i.e., phenylalanine [area under the curve (AUC) = 0.745], histidine [AUC = 0.729], proline [AUC = 0.722], lactic acid [AUC = 0.722], and carnitine [AUC = 0.714] exhibited highest potential in discriminating GH from normotensive women. CONCLUSION: The present study is the first of its kind to identify significantly altered metabolites that have the potential to discriminate between women at risk of developing GH and normotensive women across three trimesters of pregnancy. This opens up the possibility of exploring these metabolites as potential early predictive markers of GH.

Identification of Common Dysregulated Genes in COVID-19 and Hypersensitivity Pneumonitis: A Systems Biology and Machine Learning Approach.

A comprehensive knowledge on systems biology of severe acute respiratory syndrome coronavirus 2 is crucial for differential diagnosis of COVID-19. Interestingly, the radiological and pathological features of COVID-19 mimic that of hypersensitivity pneumonitis (HP), another pulmonary fibrotic phenotype. This motivated us to explore the overlapping pathophysiology of COVID-19 and HP, if any, and using a systems biology approach. Two datasets were obtained from the Gene Expression Omnibus database (GSE147507 and GSE150910) and common differentially expressed genes (DEGs) for both diseases identified. Fourteen common DEGs, significantly altered in both diseases, were found to be implicated in complement activation and growth factor activity. A total of five microRNAs (hsa-miR-1-3p, hsa-miR-20a-5p, hsa-miR-107, hsa-miR-16-5p, and hsa-miR-34b-5p) and five transcription factors (KLF6, ZBTB7A, ELF1, NFIL3, and ZBT33) exhibited highest interaction with these common genes. Next, C3, CFB, MMP-9, and IL1A were identified as common hub genes for both COVID-19 and HP. Finally, these top-ranked genes (hub genes) were evaluated using random forest classifier to discriminate between the disease and control group (coronavirus disease 2019 [COVID-19] vs. controls, and HP vs. controls). This supervised machine learning approach demonstrated 100% and 87.6% accuracy in differentiating COVID-19 from controls, and HP from controls, respectively. These findings provide new molecular leads that inform COVID-19 and HP diagnostics and therapeutics research and innovation.

Metabolomics of asthma, COPD, and asthma-COPD overlap: an overview.

The two common progressive lung diseases, asthma and chronic obstructive pulmonary disease (COPD), are the leading causes of morbidity and mortality worldwide. Asthma-COPD overlap, referred to as ACO, is another complex pulmonary disease that manifests itself with features of both asthma and COPD. The disease has no clear diagnostic or therapeutic guidelines, thereby making both diagnosis and treatment challenging. Though a number of studies on ACO have been documented, gaps in knowledge regarding the pathophysiologic mechanism of this disorder exist. Addressing this issue is an urgent need for improved diagnostic and therapeutic management of the disease. Metabolomics, an increasingly popular technique, reveals the pathogenesis of complex diseases and holds promise in biomarker discovery. This comprehensive narrative review, comprising 99 original research articles in the last five years (2017-2022), summarizes the scientific advances in terms of metabolic alterations in patients with asthma, COPD, and ACO. The analytical tools, nuclear magnetic resonance (NMR), gas chromatography-mass spectrometry (GC-MS), and liquid chromatography-mass spectrometry (LC-MS), commonly used to study the expression of the metabolome, are discussed. Challenges frequently encountered during metabolite identification and quality assessment are highlighted. Bridging the gap between phenotype and metabotype is envisioned in the future.

Risk factors associated with mortality in hypersensitivity pneumonitis: a meta-analysis.

BACKGROUND: Hypersensitivity pneumonitis (HP) related deaths have increased substantially in recent years. It is important to identify the risk factors of HP significantly associated with mortality to ensure close patient monitoring and assess disease progression. RESEARCH DESIGN AND METHODS: Extensive literature search was conducted in accordance with the PRISMA checklist. Literature search of PubMed, Embase, and Cochrane Library database between January 2009 and April 2021 using the terms 'hypersensitivity pneumonitis', 'hazard ratio', and 'mortality' identified 325 articles. A total of 22 independent original studies focusing on mortality of HP patients were assessed. RESULTS: This systematic review and meta-analysis suggests that increased age, male sex, honeycombing, and traction bronchiectasis patterns on high-resolution computed tomography (HRCT) images are the major mortality-related risk factors of patients with HP. In case of chronic HP, antigen exposure appeared to be an additional risk factor. CONCLUSIONS: The clinico-radiological risk factors of mortality identified for HP will enable effective and close monitoring of patients, prognostication, and guide toward appropriate management decisions. However, association between the type of antigen and mortality remains to be explored.

Therapeutic potential of curcumin in endometrial disorders: Current status and future perspectives.

Endometrial disorders collectively encompass a broad spectrum of pathologies, including but not limited to endometriosis, endometrial cancer and endometritis. The current therapeutic management of these diseases is associated with several limitations. This has prompted interest in the use of plant-based bioactive compounds as alternative strategies to achieve high therapeutic efficacy and avoid adverse effects. In this context, curcumin, a polyphenol abundantly present in turmeric, is gaining increasing attention for its therapeutic potential to restore homeostasis in endometrial dysfunctionality. We comprehensively review the multifaceted role of curcumin, discussing mechanistic insights in various endometrial pathologies. We also provide an in-depth analysis of the concerns and challenges associated with the role of curcumin in endometrial research and outline a road map for future investigations.

NMR metabolomic and microarray-based transcriptomic data integration identifies unique molecular signatures of hypersensitivity pneumonitis.

Hypersensitivity pneumonitis (HP) is an immune-mediated granulomatous interstitial lung disease (ILD) that results from repeated inhalation of certain antigens. Despite major advances in research, pathophysiology of the disease remains poorly understood. The present study combines metabolomic and transcriptomic data to determine alterations in HP subjects as compared with healthy controls. Metabolic signatures were identified in serum, exhaled breath condensate (EBC) and bronchoalveolar lavage fluid (BALF) of HP patients using proton nuclear magnetic resonance (NMR) metabolomics. The expression of three metabolites, i.e., lactate, pyruvate, and proline, was found to be significantly altered in all three biofluids. The potential of differential diagnosis based on these three metabolites was investigated by including a group of patients with sarcoidosis, which is another type of granulomatous ILD. In addition, differentially expressed transcriptomic fingerprints in blood samples were identified by analyzing a Gene Expression Omnibus (GEO) database. The transcriptomics analysis of these microarray-based data revealed 59 genes to be significantly dysregulated in patients with HP. Over representation analysis of the metabolites and genes of interest was performed using IMPaLA (Integrated Molecular Pathway Level Analysis) version 12. Integrated analysis of serum metabolite signatures and blood gene expression suggests dysregulation of PI3K-AKT signaling and TCA cycle pathways in these patients. This preliminary study is a step towards better understanding of the pathogenesis of HP by identification of differentially expressed metabolites and transcriptomic fingerprints. These molecular signatures may be explored as diagnostic markers for differentiating HP from other lung diseases.

Identification of novel metabolic signatures potentially involved in the pathogenesis of COPD associated pulmonary hypertension.

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) associated pulmonary hypertension (COPD-PH), one of the most prevalent forms of PH, is a major burden on the healthcare system. Although PH in COPD is usually of mild-to-moderate severity, its presence is associated with shorter survival, more frequent exacerbations and worse clinical outcomes. The pathophysiologic mechanisms responsible for PH development in COPD patients remain unclear. It is envisioned that a better understanding of the underlying mechanism will help in diagnosis and future treatment strategies. OBJECTIVES: The present study aims to determine metabolomic alterations in COPD-PH patients as compared to healthy controls. Additionally, to ensure that the dysregulated metabolites arise due to the presence of PH per se, an independent COPD cohort is included for comparison purposes. METHODS: Paired serum and exhaled breath condensate (EBC) samples were collected from male patients with COPD-PH (n = 60) in accordance with the 2015 European Society of Cardiology (ESC)/European Respiratory Society (ERS) guidelines. Age, sex and BMI matched healthy controls (n = 57) and COPD patients (n = 59) were recruited for comparison purposes. All samples were characterized using 1H nuclear magnetic resonance (NMR) spectroscopy. RESULTS: Fifteen serum and 9 EBC metabolites were found to be significantly altered in COPD-PH patients as compared to healthy controls. Lactate and pyruvate were dysregulated in both the biofluids and were further correlated with echocardiographic systolic pulmonary artery pressure (sPAP). Multivariate analysis showed distinct class separation between COPD-PH and COPD. CONCLUSIONS: The findings of this study indicate an increased energy demand in patients with COPD-PH. Furthermore, both lactate and pyruvate correlate with sPAP, indicating their importance in the clinical course of the disease.

Air pollution-induced epigenetic changes: disease development and a possible link with hypersensitivity pneumonitis.

Air pollution is a serious threat to our health and has become one of the major causes of many diseases including cardiovascular disease, respiratory disease, and cancer. The association between air pollution and various diseases has long been a topic of research interest. However, it remains unclear how air pollution actually impacts health by modulating several important cellular functions. Recently, some evidence has emerged about air pollution-induced epigenetic changes, which are linked with the etiology of various human diseases. Among several epigenetic modifications, DNA methylation represents the most prominent epigenetic alteration underlying the air pollution-induced pathogenic mechanism. Several other types of epigenetic changes, such as histone modifications, miRNA, and non-coding RNA expression, have also been found to have been linked with air pollution. Hypersensitivity pneumonitis (HP), one of the most prevalent forms of interstitial lung diseases (ILDs), is triggered by the inhalation of certain organic and inorganic substances. HP is characterized by inflammation in the tissues around the lungs' airways and may lead to irreversible lung scarring over time. This review, in addition to other diseases, attempts to understand whether certain pollutants influence HP development through such epigenetic modifications.

Proteomics in idiopathic pulmonary fibrosis: the quest for biomarkers.

Idiopathic pulmonary fibrosis (IPF) is a debilitating chronic progressive and fibrosing lung disease that culminates in the destruction of alveolar integrity and dismal prognosis. Its etiology is unknown and pathophysiology remains unclear. While great advances have been made in elucidating the pathogenesis mechanism, considerable gaps related to information on pathogenetic pathways and key protein targets involved in the clinical course of the disease exist. These issues need to be addressed for better clinical management of this highly challenging disease. Omics approach has revolutionized the entire area of disease understanding and holds promise in its translation to clinical biomarker discovery. This review outlines the contribution of proteomics towards identification of important biomarkers in IPF in terms of their clinical utility, i.e. prognosis, differential diagnosis, disease progression and treatment monitoring. The major dysregulated pathways associated with IPF are also discussed. Based on numerous proteomics studies on human and animal models, it is proposed that IPF pathogenesis involves complex interactions of several pathways such as oxidative stress, endoplasmic reticulum stress, unfolded protein response, coagulation system, inflammation, abnormal wounding, fibroblast proliferation, fibrogenesis and deposition of extracellular matrix. These pathways and their key path-changing mediators need further validation in large well-planned multi-centric trials at various geographical locations for successful development of clinical biomarkers of this confounding disease.

High-resolution computerized tomography changes in diffuse parenchymal lung disease from chronic hypersensitivity pneumonitis related to bird antigen.

BACKGROUND: Chronic hypersensitivity pneumonitis (HP) is the most common cause of diffuse parenchymal lung disease (DPLD) in India. There is no data regarding the avian antigen exposure-associated DPLD from the country. METHODS: Chronic HP from exposure to avian antigen was diagnosed when the high resolution computerized tomography (HRCT) showed features for HP and was supported by the history of exposure to pigeons, the presence of precipitin antibodies (IgG) to avian antigen in high titre with negative rheumatoid factor, antinuclear antibody, and no clinical clue for a collagen vascular disease. The HRCT changes were noted on Likert scale (0-5) in terms of affection of peripheral and/or axial involvement, reticulation, honeycombing, haze, mosaic, traction bronchiectasis, pleural reactions, features of pulmonary hypertension, and air cysts. Cardiomegaly and independent cardiac chamber enlargement were also recorded. RESULTS: The lower lobes were predominantly (65.6%) affected with similar frequency (78.1) of peripheral and axial parenchymal affection. The parenchymal changes in HRCT were haze or ground-glass opacity (100%), mosaic appearance (93.75%), reticulations (68.75%), traction bronchiectasis (34.3%), air cysts (21.8%), and honeycombing (9.37%). Pleural reactions, though not described so far, were found in 50% of cases. Features of pulmonary hypertension (87.5%), cardiomegaly (50%), left and right atrial enlargement (81.2% and 78.1%), and right ventricular enlargement (31.2%) were the common echocardiography findings. CONCLUSION: Chronic HP from avian exposure shows predominantly lower lobe involvement with haze, reticulation, features of pulmonary hypertension, and pleural reactions as common HRCT findings. The likelihood of pulmonary hypertension appears high and although honeycombing is often present, the classical UIP pattern has not been found.