International Journal of Molecular Sciences

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19 pages, 1387 KiB

Open AccessArticle

Effects of Anti-Fibrotic Drugs on Transcriptome of Peripheral Blood Mononuclear Cells in Idiopathic Pulmonary Fibrosis

by Daisuke Ishii, Takeshi Kawasaki, Hironori Sato, Koichiro Tatsumi, Takuro Imamoto, Keiichiro Yoshioka, Mitsuhiro Abe, Yoshinori Hasegawa, Osamu Ohara and Takuji Suzuki

Int. J. Mol. Sci. 2024, 25(7), 3750; https://doi.org/10.3390/ijms25073750 - 28 Mar 2024

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Abstract

Two anti-fibrotic drugs, pirfenidone (PFD) and nintedanib (NTD), are currently used to treat idiopathic pulmonary fibrosis (IPF). Peripheral blood mononuclear cells (PBMCs) are immunocompetent cells that could orchestrate cell–cell interactions associated with IPF pathogenesis. We employed RNA sequencing to examine the transcriptome signature [...] Read more.

Two anti-fibrotic drugs, pirfenidone (PFD) and nintedanib (NTD), are currently used to treat idiopathic pulmonary fibrosis (IPF). Peripheral blood mononuclear cells (PBMCs) are immunocompetent cells that could orchestrate cell–cell interactions associated with IPF pathogenesis. We employed RNA sequencing to examine the transcriptome signature in the bulk PBMCs of patients with IPF and the effects of anti-fibrotic drugs on these signatures. Differentially expressed genes (DEGs) between “patients with IPF and healthy controls” and “before and after anti-fibrotic treatment” were analyzed. Enrichment analysis suggested that fatty acid elongation interferes with TGF-β/Smad signaling and the production of oxidative stress since treatment with NTD upregulates the fatty acid elongation enzymes ELOVL6. Treatment with PFD downregulates COL1A1, which produces wound-healing collagens because activated monocyte-derived macrophages participate in the production of collagen, type I, and alpha 1 during tissue damage. Plasminogen activator inhibitor-1 (PAI-1) regulates wound healing by inhibiting plasmin-mediated matrix metalloproteinase activation, and the inhibition of PAI-1 activity attenuates lung fibrosis. DEG analysis suggested that both the PFD and NTD upregulate SERPINE1, which regulates PAI-1 activity. This study embraces a novel approach by using RNA sequencing to examine PBMCs in IPF, potentially revealing systemic biomarkers or pathways that could be targeted for therapy. Full article

(This article belongs to the Special Issue Molecular Advances and Perspectives of Lung Disease)

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14 pages, 297 KiB

Open AccessArticle

Inflammasome-Related Genetic Polymorphisms as Severity Biomarkers of COVID-19

by Verónica Pulito-Cueto, María Sebastián Mora-Gil, Diego Ferrer-Pargada, Sara Remuzgo-Martínez, Fernanda Genre, Leticia Lera-Gómez, Pilar Alonso-Lecue, Joao Carlos Batista-Liz, Sandra Tello-Mena, Beatriz Abascal-Bolado, Sheila Izquierdo, Juan José Ruiz-Cubillán, Carlos Armiñanzas-Castillo, Ricardo Blanco, Miguel A. González-Gay, Raquel López-Mejías and José M. Cifrián

Int. J. Mol. Sci. 2024, 25(7), 3731; https://doi.org/10.3390/ijms25073731 - 27 Mar 2024

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Abstract

The most critical forms of coronavirus disease 2019 (COVID-19) are associated with excessive activation of the inflammasome. Despite the COVID-19 impact on public health, we still do not fully understand the mechanisms by which the inflammatory response influences disease prognosis. Accordingly, we aimed [...] Read more.

The most critical forms of coronavirus disease 2019 (COVID-19) are associated with excessive activation of the inflammasome. Despite the COVID-19 impact on public health, we still do not fully understand the mechanisms by which the inflammatory response influences disease prognosis. Accordingly, we aimed to elucidate the role of polymorphisms in the key genes of the formation and signaling of the inflammasome as biomarkers of COVID-19 severity. For this purpose, a large and well-defined cohort of 377 COVID-19 patients with mild (n = 72), moderate (n = 84), severe (n = 100), and critical (n = 121) infections were included. A total of 24 polymorphisms located in inflammasome-related genes (NLRP3, NLRC4, NLRP1, CARD8, CASP1, IL1B, IL18, NFKB1, ATG16L1, and MIF) were genotyped in all of the patients and in the 192 healthy controls (HCs) (who were without COVID-19 at the time of and before the study) by RT-qPCR. Our results showed that patients with mild, moderate, severe, and critical COVID-19 presented similar allelic and genotypic distribution in all the variants studied. No statistically significant differences in the haplotypic distribution of NLRP3, NLRC4, NLRP1, CARD8, CASP1, IL1B, and ATG16L1 were observed between COVID-19 patients, who were stratified by disease severity. Each stratified group of patients presented a similar genetic distribution to the HCs. In conclusion, our results suggest that the inflammasome polymorphisms studied are not associated with the worsening of COVID-19. Full article

(This article belongs to the Special Issue Molecular Advances and Perspectives of Lung Disease)

19 pages, 9207 KiB

Open AccessArticle

Genetic Diversity in Bronchial Asthma Susceptibility: Exploring the Role of Vitamin D Receptor Gene Polymorphisms in Varied Geographic Contexts

by Natalia Paramonova, Ilva Trapina, Brigita Gradauskiene (Sitkauskiene), Samanta Plavina, Laura Tamasauskiene, Daina Bastyte, Ingrida Rumba-Rozenfelde, Sandra Tapina, Ieva Stakaitiene, Rasa Ugenskiene, Lawrence Shih-Hsin Wu, Jiu-Yao Wang, Miao-Hsi Hsieh, Pei-Chi Chen and Nikolajs Sjakste

Int. J. Mol. Sci. 2024, 25(3), 1943; https://doi.org/10.3390/ijms25031943 - 05 Feb 2024

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Abstract

Bronchial asthma (BA) exhibits varying prevalence across global populations, prompting a comprehensive investigation into genetic and environmental determinants. Vitamin D is a potent immunomodulator capable of suppressing inflammatory signals in several cell types involved in the asthmatic response; it exerts effects on the [...] Read more.

Bronchial asthma (BA) exhibits varying prevalence across global populations, prompting a comprehensive investigation into genetic and environmental determinants. Vitamin D is a potent immunomodulator capable of suppressing inflammatory signals in several cell types involved in the asthmatic response; it exerts effects on the immune system by binding to the nuclear vitamin D receptor (VDR). VDR gene genetic variations are affecting serum vitamin D levels with a possible role in the BA risk. The current study aimed to examine the complex interaction of various factors (genetic background, serum vitamin D levels, and geographic location) to identify differences in the influence of these factors on the susceptibility to asthma between populations at different latitudes. Focusing on Eastern European cohorts from Latvia and Lithuania and comparing them with published data on East Asian populations, we explore the impact of VDR gene polymorphisms on BA susceptibility. Genotyping four key VDR SNPs and assessing their association with 25-hydroxyvitamin D levels, our study unveils significant associations of the studied loci with the risk of asthma—both risk-reducing and increasing effects, differently distributed between Baltic and East Asian populations. The functional effects of in silico VDR gene genetic variations are also identified and discussed. Full article

(This article belongs to the Special Issue Molecular Advances and Perspectives of Lung Disease)

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24 pages, 21780 KiB

Open AccessArticle

Functional Roles of CD26/DPP4 in Bleomycin-Induced Pulmonary Hypertension Associated with Interstitial Lung Disease

by Tadasu Okaya, Takeshi Kawasaki, Shun Sato, Yu Koyanagi, Koichiro Tatsumi, Ryo Hatano, Kei Ohnuma, Chikao Morimoto, Yoshitoshi Kasuya, Yoshinori Hasegawa, Osamu Ohara and Takuji Suzuki

Int. J. Mol. Sci. 2024, 25(2), 748; https://doi.org/10.3390/ijms25020748 - 06 Jan 2024

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Abstract

Pulmonary hypertension (PH) with interstitial lung diseases (ILDs) often causes intractable conditions. CD26/Dipeptidyl peptidase-4 (DPP4) is expressed in lung constituent cells and may be related to the pathogenesis of various respiratory diseases. We aimed to clarify the functional roles of CD26/DPP4 in PH-ILD, [...] Read more.

Pulmonary hypertension (PH) with interstitial lung diseases (ILDs) often causes intractable conditions. CD26/Dipeptidyl peptidase-4 (DPP4) is expressed in lung constituent cells and may be related to the pathogenesis of various respiratory diseases. We aimed to clarify the functional roles of CD26/DPP4 in PH-ILD, paying particular attention to vascular smooth muscle cells (SMCs). Dpp4 knockout (Dpp4KO) and wild type (WT) mice were administered bleomycin (BLM) intraperitoneally to establish a PH-ILD model. The BLM-induced increase in the right ventricular systolic pressure and the right ventricular hypertrophy observed in WT mice were attenuated in Dpp4KO mice. The BLM-induced vascular muscularization in small pulmonary vessels in Dpp4KO mice was milder than that in WT mice. The viability of TGFβ-stimulated human pulmonary artery SMCs (hPASMCs) was lowered due to the DPP4 knockdown with small interfering RNA. According to the results of the transcriptome analysis, upregulated genes in hPASMCs with TGFβ treatment were related to pulmonary vascular SMC proliferation via the Notch, PI3K-Akt, and NFκB signaling pathways. Additionally, DPP4 knockdown in hPASMCs inhibited the pathways upregulated by TGFβ treatment. These results suggest that genetic deficiency of Dpp4 protects against BLM-induced PH-ILD by alleviating vascular remodeling, potentially through the exertion of an antiproliferative effect via inhibition of the TGFβ-related pathways in PASMCs. Full article

(This article belongs to the Special Issue Molecular Advances and Perspectives of Lung Disease)

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19 pages, 2959 KiB

Open AccessArticle

Different Transcriptome Features of Peripheral Blood Mononuclear Cells in Non-Emphysematous Chronic Obstructive Pulmonary Disease

by Takuro Imamoto, Takeshi Kawasaki, Hironori Sato, Koichiro Tatsumi, Daisuke Ishii, Keiichiro Yoshioka, Yoshinori Hasegawa, Osamu Ohara and Takuji Suzuki

Int. J. Mol. Sci. 2024, 25(1), 66; https://doi.org/10.3390/ijms25010066 - 20 Dec 2023

Cited by 1 | Viewed by 1448

Abstract

Non-emphysematous chronic obstructive pulmonary disease (COPD), which is defined based on chest computed tomography findings, presented different transcriptome features of peripheral blood mononuclear cells (PBMCs) compared with emphysematous COPD. Enrichment analysis of transcriptomic data in COPD demonstrated that the “Hematopoietic cell lineage” pathway [...] Read more.

Non-emphysematous chronic obstructive pulmonary disease (COPD), which is defined based on chest computed tomography findings, presented different transcriptome features of peripheral blood mononuclear cells (PBMCs) compared with emphysematous COPD. Enrichment analysis of transcriptomic data in COPD demonstrated that the “Hematopoietic cell lineage” pathway in Kyoto Encyclopedia of Genes and Genomes pathway analysis was highly upregulated, suggesting that cellular dynamic dysregulation in COPD lungs is affected by pathologically modified PBMCs. The differentially expressed genes (DEGs) upregulated in PBMCs reflected the disease state of non-emphysematous COPD. Upregulated DEGs such as XCL1, PRKCZ, TMEM102, CD200R1, and AQP1 activate T lymphocytes and eosinophils. Upregulating keratan sulfate biosynthesis and metabolic processes is associated with protection against the destruction of the distal airways. ITGA3 upregulation augments interactions with extracellular matrix proteins, and COL6A1 augments the profibrotic mast cell phenotype during alveolar collagen VI deposition. Upregulating HSPG2, PDGFRB, and PAK4 contributes to the thickening of the airway wall, and upregulating SERPINF1 expression explains the better-preserved vascular bed. Therefore, gene expression and pathway analysis in PBMCs in patients with non-emphysematous COPD represented type 2 immune responses and airway remodeling features. Therefore, these patients have asthmatic potential despite no clinical signs of asthma, in contrast to those with emphysematous COPD. Full article

(This article belongs to the Special Issue Molecular Advances and Perspectives of Lung Disease)

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Review

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43 pages, 2818 KiB

Open AccessReview

Host Transcriptional Regulatory Genes and Microbiome Networks Crosstalk through Immune Receptors Establishing Normal and Tumor Multiomics Metafirm of the Oral-Gut-Lung Axis

by Beatriz Andrea Otálora-Otálora, Juan Javier López-Rivera, Claudia Aristizábal-Guzmán, Mario Arturo Isaza-Ruget and Carlos Arturo Álvarez-Moreno

Int. J. Mol. Sci. 2023, 24(23), 16638; https://doi.org/10.3390/ijms242316638 - 23 Nov 2023

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Abstract

The microbiome has shown a correlation with the diet and lifestyle of each population in health and disease, the ability to communicate at the cellular level with the host through innate and adaptative immune receptors, and therefore an important role in modulating inflammatory [...] Read more.

The microbiome has shown a correlation with the diet and lifestyle of each population in health and disease, the ability to communicate at the cellular level with the host through innate and adaptative immune receptors, and therefore an important role in modulating inflammatory process related to the establishment and progression of cancer. The oral cavity is one of the most important interaction windows between the human body and the environment, allowing the entry of an important number of microorganisms and their passage across the gastrointestinal tract and lungs. In this review, the contribution of the microbiome network to the establishment of systemic diseases like cancer is analyzed through their synergistic interactions and bidirectional crosstalk in the oral-gut-lung axis as well as its communication with the host cells. Moreover, the impact of the characteristic microbiota of each population in the formation of the multiomics molecular metafirm of the oral-gut-lung axis is also analyzed through state-of-the-art sequencing techniques, which allow a global study of the molecular processes involved of the flow of the microbiota environmental signals through cancer-related cells and its relationship with the establishment of the transcription factor network responsible for the control of regulatory processes involved with tumorigenesis. Full article

(This article belongs to the Special Issue Molecular Advances and Perspectives of Lung Disease)

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18 pages, 1335 KiB

Open AccessReview

PANoptosis: Mechanism and Role in Pulmonary Diseases

by Shiyi Chen, Jiacheng Jiang, Tongfu Li and Longshuang Huang

Int. J. Mol. Sci. 2023, 24(20), 15343; https://doi.org/10.3390/ijms242015343 - 19 Oct 2023

Cited by 1 | Viewed by 1991

Abstract

PANoptosis is a newly defined programmed cell death (PCD) triggered by a series of stimuli, and it engages three well-learned PCD forms (pyroptosis, apoptosis, necroptosis) concomitantly. Normally, cell death is recognized as a strategy to eliminate unnecessary cells, inhibit the proliferation of invaded [...] Read more.

PANoptosis is a newly defined programmed cell death (PCD) triggered by a series of stimuli, and it engages three well-learned PCD forms (pyroptosis, apoptosis, necroptosis) concomitantly. Normally, cell death is recognized as a strategy to eliminate unnecessary cells, inhibit the proliferation of invaded pathogens and maintain homeostasis; however, vigorous cell death can cause excessive inflammation and tissue damage. Acute lung injury (ALI) and chronic obstructive pulmonary syndrome (COPD) exacerbation is related to several pathogens (e.g., influenza A virus, SARS-CoV-2) known to cause PANoptosis. An understanding of the mechanism and specific regulators may help to address the pathological systems of these diseases. This review presents our understanding of the potential mechanism of PANoptosis and the role of PANoptosis in different pulmonary diseases. Full article

(This article belongs to the Special Issue Molecular Advances and Perspectives of Lung Disease)

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15 pages, 1449 KiB

Open AccessReview

Molecular Markers of Early Immune Response in Tuberculosis: Prospects of Application in Predictive Medicine

by Anastasiia Diatlova, Natalia Linkova, Anastasia Lavrova, Yulia Zinchenko, Dmitrii Medvedev, Alexandr Krasichkov, Victoria Polyakova and Piotr Yablonskiy

Int. J. Mol. Sci. 2023, 24(17), 13261; https://doi.org/10.3390/ijms241713261 - 26 Aug 2023

Cited by 4 | Viewed by 1612

Abstract

Tuberculosis (TB) remains an important public health problem and one of the leading causes of death. Individuals with latent tuberculosis infection (LTBI) have an increased risk of developing active TB. The problem of the diagnosis of the various stages of TB and the [...] Read more.

Tuberculosis (TB) remains an important public health problem and one of the leading causes of death. Individuals with latent tuberculosis infection (LTBI) have an increased risk of developing active TB. The problem of the diagnosis of the various stages of TB and the identification of infected patients in the early stages has not yet been solved. The existing tests (the tuberculin skin test and the interferon-gamma release assay) are useful to distinguish between active and latent infections. But these tests cannot be used to predict the development of active TB in individuals with LTBI. The purpose of this review was to analyze the extant data of the interaction of M. tuberculosis with immune cells and identify molecular predictive markers and markers of the early stages of TB. An analysis of more than 90 sources from the literature allowed us to determine various subpopulations of immune cells involved in the pathogenesis of TB, namely, macrophages, dendritic cells, B lymphocytes, T helper cells, cytotoxic T lymphocytes, and NK cells. The key molecular markers of the immune response to M. tuberculosis are cytokines (IL-1β, IL-6, IL-8, IL-10, IL-12, IL-17, IL-22b, IFNɣ, TNFa, and TGFß), matrix metalloproteinases (MMP-1, MMP-3, and MMP-9), and their inhibitors (TIMP-1, TIMP-2, TIMP-3, and TIMP-4). It is supposed that these molecules could be used as biomarkers to characterize different stages of TB infection, to evaluate the effectiveness of its treatment, and as targets of pharmacotherapy. Full article

(This article belongs to the Special Issue Molecular Advances and Perspectives of Lung Disease)

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