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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 September 2023) | Viewed by 35490

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Dr. Paolo Cameli

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Respiratory Diseases and Lung Transplantation Unit, Department of Medicine, Surgery and Neurosciences, University Hospital of Siena, 53100 Siena, Italy
Interests: interstitial lung disease; KL-6; lung transplant; vasculitis; myositis
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Special Issue Information

Dear Colleagues,

A novel era in respiratory medicine is approaching. New innovative scientific techniques, including omics sciences, as well as the analysis and interpretation of Big Data through the implementation of artificial intelligence and bioinformatic algorithms, have already demonstrated tremendous and unseen perspectives for the comprehension of the pathobiology of many respiratory disorders

This Special Issue of IJMS represents a call for articles that would provide new insights into the molecular aspects of physiology and biochemistry of respiratory diseases. Submissions with an emphasis on emerging approaches, such as omics sciences (genomics, metabolomics, proteomics, lipidomics, and glycomics) and cytofluorimetric assays, are welcome. The molecular and immunological bases of diseases are often poorly understood, and so are the effects of aging, gender, smoking, pollution, and pharmaceutical intervention.

This Special issue aims to expand the current comprehension of the molecular pathogenesis of lung diseases and the biomolecular effects of the newest currently approved therapeutical approaches. Experimental studies, including in vitro and in vivo models, review articles, and clinical studies, are all eligible for consideration.

Dr. Paolo Cameli
Guest Editor

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Keywords

severe asthma
COPD
lung cancer
pathology
molecular biomarkers
interstitial lung diseases
immunobiology
omics
prognosis
pathogenesis
proteomics
genetics

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Published Papers (10 papers)

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Research

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11 pages, 1430 KiB

Open AccessArticle

Predictive Role of Cytokine and Adipokine Panel in Hospitalized COVID-19 Patients: Evaluation of Disease Severity, Survival and Lung Sequelae

by Laura Bergantini, Miriana d’Alessandro, Sara Gangi, Francesco Bianchi, Paolo Cameli, Beatrice Perea, Martina Meocci, Gaia Fabbri, Sofia Marrucci, Moftah Ederbali and Elena Bargagli

Int. J. Mol. Sci. 2023, 24(16), 12994; https://doi.org/10.3390/ijms241612994 - 20 Aug 2023

Cited by 6 | Viewed by 1487

Abstract

Coronavirus disease 2019 (COVID-19) may determine a multisystemic chronic syndrome after resolution of SARS-CoV-2 infection in a significant percentage of patients. Persistent cytokine dysregulation can contribute to long-lasting inflammation and tissue damage, resulting in the diverse, often debilitating symptoms experienced by some patients (so-called long COVID syndrome). The aim of our study was to evaluate the value of a panel of serum biomarkers of severity and prognosis in patients hospitalized for COVID-19 and also as predictive factors for the development of post-COVID lung sequelae after discharge from the hospital. All blood sampling was performed in the first 24 h after admission to the hospital. Serum analyte concentrations of IL-4, IL-2, CXCL10 (IP-10), IL-1β, TNF-α, CCL2 (MCP-1), IL-17A, IL-6, IL-10, IFN-γ, IL-12p70 and TGF-β1 were quantified by bead-based multiplex LEGENDplex™ analysis and commercially available ELISA kits. A total of 108 COVID-19 patients were enrolled in the study. Comparative analysis of these proteins showed higher levels of TGF-β and IL-6 and lower levels of RBP-4 and IL-10 in the severe group. Age, adiponectin, IL-8 and IL-32 resulted as the best predictors for survival. Moreover, IL-1β, IL17A, TNF-α, TGF-β, IL-4 and IL-6 were significantly higher in patients who showed HRCT evidence of fibrotic interstitial alterations at follow-up than patients who did not. The initial inflammatory status of patients on admission to the hospital with COVID-19, as reflected by the present panel of adipose tissue-related biomarkers and cytokines, offered insights into medium-term prognosis. Full article

(This article belongs to the Special Issue Advances in the Molecular Biology of Lung Disease)

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15 pages, 1962 KiB

Open AccessArticle

Quantifying Functional Impairment of ABCA3 Variants Associated with Interstitial Lung Disease

by Xiaohua Yang, Christina K. Rapp, Yang Li, Maria Forstner and Matthias Griese

Int. J. Mol. Sci. 2023, 24(8), 7554; https://doi.org/10.3390/ijms24087554 - 20 Apr 2023

Cited by 7 | Viewed by 1527

Abstract

ATP-binding cassette subfamily A member 3 (ABCA3) is a lipid transporter within alveolar type II cells. Patients with bi-allelic variants in ABCA3 may suffer from a variable severity of interstitial lung disease. We characterized and quantified ABCA3 variants’ overall lipid transport function by assessing the in vitro impairment of its intracellular trafficking and pumping activity. We expressed the results relative to the wild type, integrated the quantitative readouts from eight different assays and used newly generated data combined with previous results to correlate the variants’ function and clinical phenotype. We differentiated normal (within 1 normalized standard deviation (nSD) of the wild-type mean), impaired (within 1 to 3 nSD) and defective (beyond 3 nSD) variants. The transport of phosphatidylcholine from the recycling pathway into ABCA3⁺ vesicles proved sensitive to the variants’ dysfunction. The sum of the quantitated trafficking and pumping predicted a clinical outcome. More than an approximately 50% loss of function was associated with considerable morbidity and mortality. The in vitro quantification of ABCA3 function enables detailed variant characterization, substantially improves the phenotype prediction of genetic variants and possibly supports future treatment decisions. Full article

(This article belongs to the Special Issue Advances in the Molecular Biology of Lung Disease)

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16 pages, 9980 KiB

Open AccessArticle

Matrix Metallopeptidase-Gene Signature Predicts Stage I Lung Adenocarcinoma Survival Outcomes

by Chia-Hsin Liu and Yuanpu Peter Di

Int. J. Mol. Sci. 2023, 24(3), 2382; https://doi.org/10.3390/ijms24032382 - 25 Jan 2023

Cited by 2 | Viewed by 2026

Abstract

Tumor recurrence poses a significant challenge to the clinical management of stage I lung adenocarcinoma after curative surgical resection. Matrix metalloproteinases (MMPs) increase expression and correlate with recurrence and metastasis in surgically resected non-small cell lung cancer. However, the impact of MMPs on survival outcome varies, and their roles in patients with stage I lung adenocarcinoma remain unclear. In two discovery cohorts, we first analyzed 226 stage I–II lung adenocarcinoma cases in the GSE31210 cohort using a clustering-based method and identified a 150-gene MMP cluster with increased expression in tumors associated with worse survival outcomes. A similar analysis was performed on 517 lung adenocarcinoma cases in the Cancer Genome Atlas cohort. A 185-gene MMP cluster was identified, which also showed increased expression in tumors and correlated with poor survival outcomes. We further streamlined from the discovery cohorts a 36-gene MMP signature significantly associated with recurrence and worse overall survival in patients with stage I lung adenocarcinoma after surgical resection. After adjusting for covariates, the high MMP-gene signature expression remained an independent risk factor. In addition, the MMP-gene signature showed enrichment in epidermal growth factor receptor wild-type lung tumors, especially for those with Kirsten rat sarcoma virus mutations. Using an independent validation cohort, we further validated the MMP-gene signature in 70 stage I lung adenocarcinoma cases. In conclusion, MMP-gene signature is a potential predictive and prognostic biomarker to stratify patients with stage I lung adenocarcinoma into subgroups based on their risk of recurrence for aiding physicians in deciding the personalized adjuvant therapeutics. Full article

(This article belongs to the Special Issue Advances in the Molecular Biology of Lung Disease)

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14 pages, 1714 KiB

Open AccessArticle

Plasma Cytokine Profiling Reveals Differences between Silicotic Patients with Simple Silicosis and Those with Progressive Massive Fibrosis Caused by Engineered Stone

by Antonio Campos-Caro, Gema Jiménez-Gómez, Alejandro García-Núñez, Antonio Hidalgo-Molina and Antonio León-Jiménez

Int. J. Mol. Sci. 2023, 24(2), 1541; https://doi.org/10.3390/ijms24021541 - 12 Jan 2023

Cited by 1 | Viewed by 1870

Abstract

Engineered stone silicosis has become an occupational epidemic disease that progresses rapidly to progressive massive fibrosis with respiratory failure and death, and there is no effective treatment. Silica deposition in the lung triggers a series of inflammatory reactions with the participation of multiple cytokines and cellular mediators whose role in the development and progression of the disease is largely unknown. We hypothesized that differences in plasma cytokine levels exist between patients diagnosed with simple silicosis (SS) and patients diagnosed with progressive massive fibrosis (PMF). Plasma samples from 91 ES silicosis patients, diagnosed and classified by chest radiography and/or high-resolution computed tomography with SS (n = 53) and PMF (n = 38), were assayed by multiplex assays for levels of 34 cytokines. Additionally, a healthy volunteer control group (n = 22) was included. Plasma levels of a high number of cytokines were significantly higher in subjects with silicosis than in healthy control subjects. Moreover, the levels of IL-1RA, IL-8, IL-10, IL-16, IL-18, TNF-α, MIP-1α, G-CSF and VEGF were significantly elevated in PMF compared to SS patients. This study shows that plasma cytokine levels differ between healthy people and silicosis patients, and some of them are also significantly elevated in patients with PMF compared with patients with SS, which could indicate their involvement in the severity of the disease, be considered as biomarkers and could be explored as future therapeutic targets for the disease. Full article

(This article belongs to the Special Issue Advances in the Molecular Biology of Lung Disease)

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26 pages, 6112 KiB

Open AccessArticle

N-acetylcysteine Reduces Inflammasome Activation Induced by SARS-CoV-2 Proteins In Vitro

by Javier Milara, Fernando Martínez-Expósito, Paula Montero, Inés Roger, Maria Amparo Bayarri, Pilar Ribera, Miriam Natsuki Oishi-Konari, Jose Ramón Alba-García, Enrique Zapater and Julio Cortijo

Int. J. Mol. Sci. 2022, 23(23), 14518; https://doi.org/10.3390/ijms232314518 - 22 Nov 2022

Cited by 11 | Viewed by 2860

Abstract

Inflammasome activation is one of the first steps in initiating innate immune responses. In this work, we studied the activation of inflammasomes in the airways of critically ill COVID-19 patients and the effects of N-acetylcysteine (NAC) on inflammasomes. Tracheal biopsies were obtained from critically ill patients without COVID-19 and no respiratory disease (control, n = 32), SARS-CoV-2 B.1 variant (n = 31), and B.1.1.7 VOC alpha variant (n = 20) patients. Gene expression and protein expression were measured by RT-qPCR and immunohistochemistry. Macrophages and bronchial epithelial cells were stimulated with different S, E, M, and N SARS-CoV-2 recombinant proteins in the presence or absence of NAC. NLRP3 inflammasome complex was over-expressed and activated in the COVID-19 B.1.1.7 VOC variant and associated with systemic inflammation and 28-day mortality. TLR2/MyD88 and redox NOX4/Nrf2 ratio were also over-expressed in the COVID-19 B.1.1.7 VOC variant. The combination of S-E-M SARS-CoV-2 recombinant proteins increased cytokine release in macrophages and bronchial epithelial cells through the activation of TLR2. NAC inhibited SARS-CoV-2 mosaic (S-E-M)-induced cytokine release and inflammasome activation. In summary, inflammasome is over-activated in severe COVID-19 and increased in B.1.1.7 VOC variant. In addition, NAC can reduce inflammasome activation induced by SARS-CoV-2 in vitro, which may be of potential translational value in COVID-19 patients. Full article

(This article belongs to the Special Issue Advances in the Molecular Biology of Lung Disease)

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15 pages, 3272 KiB

Open AccessArticle

Airway Smooth Muscle Cell Mitochondria Damage and Mitophagy in COPD via ERK1/2 MAPK

by Lei Fang, Ming Zhang, Junling Li, Liang Zhou, Michael Tamm and Michael Roth

Int. J. Mol. Sci. 2022, 23(22), 13987; https://doi.org/10.3390/ijms232213987 - 12 Nov 2022

Cited by 16 | Viewed by 2664

Abstract

Chronic obstructive pulmonary disease (COPD) is characterized by irreversible deterioration of the airway wall. Cigarette smoking is the major trigger, and in vitro studies showed that cigarette smoke extract (CSE) induced mitophagy in airway epithelial cells via oxidative stress, but this mechanism was not studied in airway smooth muscle cells (ASMCs). Primary ASMCs isolated from COPD patients or non-disease donors were investigated for CSE-induced remodeling and mitochondria structure. Proteins were assessed by Western blots for remodeling: collagen type-I, α-smooth muscle actin (α-SMA) and fibronectin; autophagy: beclin-1, protein62 (p62), light chain (LC)3A/B; mitochondria activity: mitochondrially encoded cytochrome c oxidase II & -IV (MTCO2, MTCO4), peroxisome proliferator activated receptor gamma coactivator 1α (PGC-1α); lysosomes: early endosome antigen 1, lysosome activated membrane protein 1; and cell signaling: extracellular signal regulated kinase (ERK1/2). Lysotracker and Mitotracker were used to monitor mitochondria morphology and organelle co-localization. Compared with controls, untreated COPD ASMCs showed lower collagen type-I and α-SMA expressions, but increased fibronectin levels. CSE further downregulated collagen type-I and α-SMA expression, but upregulated fibronectin. CSE decreased PGC-1α, MTCO2, and MTCO4, but increased beclin-1, p62, and LC3. CSE upregulated mitophagy and lysosomes activity via ERK1/2 phosphorylation. In vitro, cigarette smoke induced the deterioration of ASMCs, which might explain the tissue loss and structural remodeling in COPD bronchi. The results suggest that preventing exceeded mitophagy in ASMCs might present a novel therapeutic target for COPD. Full article

(This article belongs to the Special Issue Advances in the Molecular Biology of Lung Disease)

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Review

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23 pages, 1950 KiB

Open AccessReview

Etiology and Pathogenesis of Rheumatoid Arthritis-Interstitial Lung Disease

by Yerin Kim, Hyung-In Yang and Kyoung-Soo Kim

Int. J. Mol. Sci. 2023, 24(19), 14509; https://doi.org/10.3390/ijms241914509 - 25 Sep 2023

Cited by 9 | Viewed by 4340

Abstract

Interstitial lung disease (ILD) is one of the most serious extra-articular complications of rheumatoid arthritis (RA), which increases the mortality of RA. Because the pathogenesis of RA-ILD remains poorly understood, appropriate therapeutic strategies and biomarkers have not yet been identified. Thus, the goal of this review was to summarize and analyze the reported data on the etiology and pathogenesis of RA-ILD. The incidence of RA-ILD increases with age, and is also generally higher in men than in women and in patients with specific genetic variations and ethnicity. Lifestyle factors associated with an increased risk of RA-ILD include smoking and exposure to pollutants. The presence of an anti-cyclic citrullinated peptide antibody, high RA disease activity, and rheumatoid factor positivity also increase the risk of RA-ILD. We also explored the roles of biological processes (e.g., fibroblast–myofibroblast transition, epithelial–mesenchymal transition, and immunological processes), signaling pathways (e.g., JAK/STAT and PI3K/Akt), and the histopathology of RA involved in RA-ILD pathogenesis based on published preclinical and clinical models of RA-ILD in animal and human studies. Full article

(This article belongs to the Special Issue Advances in the Molecular Biology of Lung Disease)

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17 pages, 623 KiB

Open AccessReview

BRD4 as a Therapeutic Target in Pulmonary Diseases

by Xia Guo, Ayobami Olajuyin, Torry A. Tucker, Steven Idell and Guoqing Qian

Int. J. Mol. Sci. 2023, 24(17), 13231; https://doi.org/10.3390/ijms241713231 - 25 Aug 2023

Cited by 3 | Viewed by 2628

Abstract

Bromodomain and extra-terminal domain (BET) proteins are epigenetic modulators that regulate gene transcription through interacting with acetylated lysine residues of histone proteins. BET proteins have multiple roles in regulating key cellular functions such as cell proliferation, differentiation, inflammation, oxidative and redox balance, and immune responses. As a result, BET proteins have been found to be actively involved in a broad range of human lung diseases including acute lung inflammation, asthma, pulmonary arterial hypertension, pulmonary fibrosis, and chronic obstructive pulmonary disease (COPD). Due to the identification of specific small molecular inhibitors of BET proteins, targeting BET in these lung diseases has become an area of increasing interest. Emerging evidence has demonstrated the beneficial effects of BET inhibitors in preclinical models of various human lung diseases. This is, in general, largely related to the ability of BET proteins to bind to promoters of genes that are critical for inflammation, differentiation, and beyond. By modulating these critical genes, BET proteins are integrated into the pathogenesis of disease progression. The intrinsic histone acetyltransferase activity of bromodomain-containing protein 4 (BRD4) is of particular interest, seems to act independently of its bromodomain binding activity, and has implication in some contexts. In this review, we provide a brief overview of the research on BET proteins with a focus on BRD4 in several major human lung diseases, the underlying molecular mechanisms, as well as findings of targeting BET proteins using pharmaceutical inhibitors in different lung diseases preclinically. Full article

(This article belongs to the Special Issue Advances in the Molecular Biology of Lung Disease)

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18 pages, 1430 KiB

Open AccessReview

Non-Small Cell Lung Cancer Targeted Therapy: Drugs and Mechanisms of Drug Resistance

by Jiajia Wu and Zhenghong Lin

Int. J. Mol. Sci. 2022, 23(23), 15056; https://doi.org/10.3390/ijms232315056 - 1 Dec 2022

Cited by 69 | Viewed by 13080

Abstract

The advent of precision medicine has brought light to the treatment of non-small cell lung cancer (NSCLC), expanding the options for patients with advanced NSCLC by targeting therapy through genetic and epigenetic cues. Tumor driver genes in NSCLC patients have been uncovered one by one, including epidermal growth factor receptor (EGFR), mesenchymal lymphoma kinase (ALK), and receptor tyrosine kinase ROS proto-oncogene 1 (ROS1) mutants. Antibodies and inhibitors that target the critical gene-mediated signaling pathways that regulate tumor growth and development are anticipated to increase patient survival and quality of life. Targeted drugs continue to emerge, with as many as two dozen approved by the FDA, and chemotherapy and targeted therapy have significantly improved patient prognosis. However, resistance due to cancer drivers’ genetic alterations has given rise to significant challenges in treating patients with metastatic NSCLC. Here, we summarized the main targeted therapeutic sites of NSCLC drugs and discussed their resistance mechanisms, aiming to provide new ideas for follow-up research and clues for the improvement of targeted drugs. Full article

(This article belongs to the Special Issue Advances in the Molecular Biology of Lung Disease)

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Other

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16 pages, 6368 KiB

Open AccessCase Report

Single-Cell Profiling of Cells in the Lung of a Patient with Chronic Hypersensitivity Pneumonitis Reveals Inflammatory Niche with Abundant CD39+ T Cells with Functional ATPase Phenotype: A Case Study

by Tharushi Ayanthika de Silva, Simon Apte, Joanne Voisey, Kirsten Spann, Maxine Tan, Chandima Divithotawela, Daniel Chambers and Brendan O’Sullivan

Int. J. Mol. Sci. 2023, 24(19), 14442; https://doi.org/10.3390/ijms241914442 - 22 Sep 2023

Cited by 2 | Viewed by 1785

Abstract

This study investigated immune cell characteristics in chronic hypersensitivity pneumonitis (HP), focusing on CD39-expressing cells’ impact on inflammation and tissue remodelling. Lung tissue from an HP patient was analysed using single-cell transcriptomics, flow cytometry, and gene expression profiling. The tissue revealed diverse cell types like macrophages, T cells, fibroblasts, and regulatory T cells (Tregs). CD39-expressing Tregs exhibited heightened ATP hydrolysis capacity and regulatory gene expression. CD39hi cells displayed markers of both Tregs and proinflammatory Th17 cells, suggesting transitional properties. Communication networks involving molecules like SPP1, collagen, CSF1, and IL-1β were identified, hinting at interactions between cell types in HP pathogenesis. This research provides insights into the immune response and cell interactions in chronic HP. CD39-expressing cells dual nature as Tregs and Th17 cells suggests a role in modulating lung inflammation, potentially affecting disease progression. These findings lay the groundwork for further research, underscoring CD39-expressing cells as potential therapeutic targets in HP. Full article

(This article belongs to the Special Issue Advances in the Molecular Biology of Lung Disease)

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