Assessment on the lung injury of mice posed by airborne PM2.5 collected from developing area in China and associated molecular mechanisms by integrated analysis of mRNA-seq and miRNA-seq

Abstract Background & aimsSome epidemiological investigations have revealed airborne fine particulate matter (PM2.5) could induce adverse effects on respiratory system of human. However, the experimental evidences of the harmful effect of PM2.5 from mid-scale city in China and associated molecular mechanisms was still scarce. In this study, we aimed to evaluate the adverse effect on the lung system of PM2.5 collected from mid-city of China and elucidate the underlying molecular mechanism through mRNA-seq and microRNA-seq integrated analysis.MethodsWe exposed male Balb/C mice to PM2.5 collected from Baoji city, China for 8 weeks (298.52 ± 25.86 μg/m3) using a whole-body exposure system. Micro-CT and histopathological analyses were performed to determine the morphology and histopathology changes of lung tissues induced by PM2.5. Transcriptome (both mRNA and microRNA) sequencing and the immunohistochemistry assay were performed to reveal the associated underlying mechanisms. The contents of PAHs absorbed in the PM2.5, as well as the pearson correlation index between it and the target genes and microRNA were examined.ResultsObvious lung injury including pulmonary dysfunction, immunological responses, and fibrosis were observed from the PM2.5 exposure group. The content of leucocyte of lung tissue was significantly increased. PM2.5 mainly induced immune pathways including B cell receptor signaling and cell adhesion molecules (CAMs). The expression levels of the associated genes and microRNA were verified using RT-qPCR. The protein expression of CD19, CD81, and PIK3CD involved into B cell receptor signaling significantly increased in exposure group. The concentrations of benzo(a)pyrene (BaP) showed a marked correlationship with the genes and microRNA. ConclusionsPM2.5 from the mid-scale city of China caused adverse effects on lung system of mice, which was much stronger than the mega city, indicating the health risk of the air pollution in the developing area should be paid more attention. The toxicity of PM2.5 may associated with immune system response. This work for the first time provided a new sight into the molecular mechanism of PM2.5 toxicity on lung system using transcriptomics integrated analysis and help further to develop effective measures to prevent air pollution associated lung disease, especially in the developing area in China.

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Nano-Curcumin Regulates p53 Phosphorylation and PAI-1 Expression during Bleomycin Induced Injury in Alveolar Basal Epithelial Cells

Current Bioactive Compounds ◽

10.2174/1573407214666180727093612 ◽

2020 ◽

Vol 16 (1) ◽

pp. 85-89

Author(s):

Mahesh M. Gouda ◽

Ashwini Prabhu ◽

Varsha Reddy S.V. ◽

Rafa Jahan ◽

Yashodhar P. Bhandary

Keyword(s):

Epithelial Cells ◽

Lung Injury ◽

Molecular Mechanisms ◽

A549 Cells ◽

Plasminogen Activator Inhibitor ◽

Underlying Mechanism ◽

Protective Role ◽

Alveolar Epithelial Cells ◽

Cellular Damage

Background: Bleomycin (BLM) is known to cause DNA damage in the Alveolar Epithelial Cells (AECs). It is reported that BLM is involved in the up-regulation of inflammatory molecules such as neutrophils, macrophages, chemokines and cytokines. The complex underlying mechanism for inflammation mediated progression of lung injury is still unclear. This investigation was designed to understand the molecular mechanisms associated with p53 mediated modulation of Plasminogen Activator Inhibitor-I (PAI-I) expression and its regulation by nano-curcumin formulation. Methods: A549 cells were treated with BLM to cause the cellular damage in vitro and commercially available nano-curcumin formulation was used as an intervention. Cytotoxic effect of nano-curcumin was analyzed using Methyl Thiazolyl Tetrazolium (MTT) assay. Protein expressions were analyzed using western blot to evaluate the p53 mediated changes in PAI-I expression. Results: Nano-curcumin showed cytotoxicity up to 88.5 % at a concentration of 20 μg/ml after 48 h of treatment. BLM exposure to the cells activated the phosphorylation of p53, which in turn increased PAII expression. Nano-curcumin treatment showed a protective role against phosphorylation of p53 and PAI-I expression, which in turn regulated the fibro-proliferative phase of injury induced by bleomycin. Conclusion: Nano-curcumin could be used as an effective intervention to regulate the severity of lung injury, apoptosis of AECs and fibro-proliferation during pulmonary injury.

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Comprehensive Analysis of Transcriptome and Metabolome Reveals the Flavonoid Metabolic Pathway Is Associated with Fruit Peel Coloration of Melon

Molecules ◽

10.3390/molecules26092830 ◽

2021 ◽

Vol 26 (9) ◽

pp. 2830

Author(s):

Aiai Zhang ◽

Jing Zheng ◽

Xuemiao Chen ◽

Xueyin Shi ◽

Huaisong Wang ◽

...

Keyword(s):

Molecular Mechanisms ◽

Comprehensive Analysis ◽

Differentially Expressed ◽

Integrated Analysis ◽

Fruit Peel ◽

External Quality ◽

Color Formation ◽

Peel Color ◽

Dark Green

The peel color is an important external quality of melon fruit. To explore the mechanisms of melon peel color formation, we performed an integrated analysis of transcriptome and metabolome with three different fruit peel samples (grey-green ‘W’, dark-green ‘B’, and yellow ‘H’). A total of 40 differentially expressed flavonoids were identified. Integrated transcriptomic and metabolomic analyses revealed that flavonoid biosynthesis was associated with the fruit peel coloration of melon. Twelve differentially expressed genes regulated flavonoids synthesis. Among them, nine (two 4CL, F3H, three F3′H, IFS, FNS, and FLS) up-regulated genes were involved in the accumulation of flavones, flavanones, flavonols, and isoflavones, and three (2 ANS and UFGT) down-regulated genes were involved in the accumulation of anthocyanins. This study laid a foundation to understand the molecular mechanisms of melon peel coloration by exploring valuable genes and metabolites.

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Early alterations of neurovascular unit in the retina in mouse models of tauopathy

Acta Neuropathologica Communications ◽

10.1186/s40478-021-01149-y ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Fan Xia ◽

Yonju Ha ◽

Shuizhen Shi ◽

Yi Li ◽

Shengguo Li ◽

...

Keyword(s):

Transgenic Mice ◽

Mouse Models ◽

Molecular Mechanisms ◽

Early Stage ◽

Leukocyte Adhesion ◽

Neurovascular Unit ◽

Integrated Analysis ◽

Therapeutic Effects ◽

Retinal Ganglion ◽

Potential Biomarker

AbstractThe retina, as the only visually accessible tissue in the central nervous system, has attracted significant attention for evaluating it as a biomarker for neurodegenerative diseases. Yet, most of studies focus on characterizing the loss of retinal ganglion cells (RGCs) and degeneration of their axons. There is no integrated analysis addressing temporal alterations of different retinal cells in the neurovascular unit (NVU) in particular retinal vessels. Here we assessed NVU changes in two mouse models of tauopathy, P301S and P301L transgenic mice overexpressing the human tau mutated gene, and evaluated the therapeutic effects of a tau oligomer monoclonal antibody (TOMA). We found that retinal edema and breakdown of blood–retina barrier were observed at the very early stage of tauopathy. Leukocyte adhesion/infiltration, and microglial recruitment/activation were constantly increased in the retinal ganglion cell layer of tau transgenic mice at different ages, while Müller cell gliosis was only detected in relatively older tau mice. Concomitantly, the number and function of RGCs progressively decreased during aging although they were not considerably altered in the very early stage of tauopathy. Moreover, intrinsically photosensitive RGCs appeared more sensitive to tauopathy. Remarkably, TOMA treatment in young tau transgenic mice significantly attenuated vascular leakage, inflammation and RGC loss. Our data provide compelling evidence that abnormal tau accumulation can lead to pathology in the retinal NVU, and vascular alterations occur more manifest and earlier than neurodegeneration in the retina. Oligomeric tau-targeted immunotherapy has the potential to treat tau-induced retinopathies. These data suggest that retinal NVU may serve as a potential biomarker for diagnosis and staging of tauopathy as well as a platform to study the molecular mechanisms of neurodegeneration.

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Molecular Mechanisms of Oxygen-Induced Lung Injury

Chronic Lung Disease in Early Infancy ◽

10.1201/b14831-34 ◽

1999 ◽

pp. 771-799

Keyword(s):

Lung Injury ◽

Molecular Mechanisms

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Integrated Analysis of lncRNAs, mRNAs, and TFs to Identify Regulatory Networks Underlying MAP Infection in Cattle

Frontiers in Genetics ◽

10.3389/fgene.2021.668448 ◽

2021 ◽

Vol 12 ◽

Author(s):

Maryam Heidari ◽

Abbas Pakdel ◽

Mohammad Reza Bakhtiarizadeh ◽

Fariba Dehghanian

Keyword(s):

Regulatory Networks ◽

Molecular Mechanisms ◽

Enrichment Analysis ◽

Johne's Disease ◽

Johne’S Disease ◽

Functional Enrichment ◽

Integrated Analysis ◽

Complex Nature ◽

Hub Genes ◽

Cis And Trans

Johne’s disease is a chronic infection of ruminants that burdens dairy herds with a significant economic loss. The pathogenesis of the disease has not been revealed clearly due to its complex nature. In order to achieve deeper biological insights into molecular mechanisms involved in MAP infection resulting in Johne’s disease, a system biology approach was used. As far as is known, this is the first study that considers lncRNAs, TFs, and mRNAs, simultaneously, to construct an integrated gene regulatory network involved in MAP infection. Weighted gene coexpression network analysis (WGCNA) and functional enrichment analysis were conducted to explore coexpression modules from which nonpreserved modules had altered connectivity patterns. After identification of hub and hub-hub genes as well as TFs and lncRNAs in the nonpreserved modules, integrated networks of lncRNA-mRNA-TF were constructed, and cis and trans targets of lncRNAs were identified. Both cis and trans targets of lncRNAs were found in eight nonpreserved modules. Twenty-one of 47 nonpreserved modules showed significant biological processes related to the immune system and MAP infection. Some of the MAP infection’s related pathways in the most important nonpreserved modules comprise “positive regulation of cytokine-mediated signaling pathway,” “negative regulation of leukocyte migration,” “T-cell differentiation,” “neutrophil activation,” and “defense response.” Furthermore, several genes were identified in these modules, including SLC11A1, MAPK8IP1, HMGCR, IFNGR1, CMPK2, CORO1A, IRF1, LDLR, BOLA-DMB, and BOLA-DMA, which are potentially associated with MAP pathogenesis. This study not only enhanced our knowledge of molecular mechanisms behind MAP infection but also highlighted several promising hub and hub-hub genes involved in macrophage-pathogen interaction.

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Emodin protects against intestinal and lung injury induced by acute intestinal injury by modulating SP-A and TLR4/NF-κB pathway

Bioscience Reports ◽

10.1042/bsr20201605 ◽

2020 ◽

Vol 40 (9) ◽

Author(s):

Jingli Qian ◽

Guoping Li ◽

Xiaosheng Jin ◽

Chunfang Ma ◽

Wanru Cai ◽

...

Keyword(s):

Lung Injury ◽

Western Blot ◽

Molecular Mechanisms ◽

Mrna Level ◽

Intestinal Injury ◽

Terminal Deoxynucleotidyl Transferase ◽

Enzyme Linked Immunosorbent Assay ◽

Tunel Staining ◽

Group Model ◽

Expression Levels

Abstract Objective: Our aim was to investigate the effect of emodin on intestinal and lung injury induced by acute intestinal injury in rats and explore potential molecular mechanisms. Methods: Healthy male Sprague–Dawley (SD) rats were randomly divided into five groups (n=10, each group): normal group; saline group; acute intestinal injury model group; model + emodin group; model+NF-κB inhibitor pynolidine dithiocarbamate (PDTC) group. Histopathological changes in intestine/lung tissues were observed by Hematoxylin and Eosin (H&E) and terminal deoxynucleotidyl transferase biotin-dUTP nick-end labeling (TUNEL) staining. Serum IKBα, p-IKBα, surfactant protein-A (SP-A) and toll-like receptor 4 (TLR4) levels were examined using enzyme-linked immunosorbent assay (ELISA). RT-qPCR was performed to detect the mRNA expression levels of IKBα, SP-A and TLR4 in intestine/lung tissues. Furthermore, the protein expression levels of IKBα, p-IKBα, SP-A and TLR4 were detected by Western blot. Results: The pathological injury of intestinal/lung tissues was remarkedly ameliorated in models treated with emodin and PDTC. Furthermore, the intestinal/lung injury scores were significantly decreased after emodin or PDTC treatment. TUNEL results showed that both emodin and PDTC treatment distinctly attenuated the apoptosis of intestine/lung tissues induced by acute intestinal injury. At the mRNA level, emodin significantly increased the expression levels of SP-A and decreased the expression levels of IKBα and TLR4 in intestine/lung tissues. According to ELISA and Western blot, emodin remarkedly inhibited the expression of p-IKBα protein and elevated the expression of SP-A and TLR4 in serum and intestine/lung tissues induced by acute intestinal injury. Conclusion: Our findings suggested that emodin could protect against intestinal and lung injury induced by acute intestinal injury by modulating SP-A and TLR4/NF-κB pathway.

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Exposure to mechanical ventilation promotes tolerance to ventilator-induced lung injury by Ccl3 downregulation

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00193.2015 ◽

2015 ◽

Vol 309 (8) ◽

pp. L847-L856 ◽

Cited By ~ 7

Author(s):

Jorge Blázquez-Prieto ◽

Inés López-Alonso ◽

Laura Amado-Rodríguez ◽

Estefanía Batalla-Solís ◽

Adrián González-López ◽

...

Keyword(s):

High Pressure ◽

Lung Injury ◽

Molecular Mechanisms ◽

Peak Pressure ◽

Lung Damage ◽

Previous Exposure ◽

Neutrophilic Infiltration ◽

Ventilator Induced Lung Injury ◽

Inflammatory Protein ◽

Albumin Content

Inflammation plays a key role in the development of ventilator-induced lung injury (VILI). Preconditioning with a previous exposure can damp the subsequent inflammatory response. Our objectives were to demonstrate that tolerance to VILI can be induced by previous low-pressure ventilation, and to identify the molecular mechanisms responsible for this phenomenon. Intact 8- to 12-wk-old male CD1 mice were preconditioned with 90 min of noninjurious ventilation [peak pressure 17 cmH2O, positive end-expiratory pressure (PEEP) 2 cmH2O] and extubated. Seven days later, preconditioned mice and intact controls were submitted to injurious ventilation (peak pressure 20 cmH2O, PEEP 0 cmH2O) for 2 h to induce VILI. Preconditioned mice showed lower histological lung injury scores, bronchoalveolar lavage albumin content, and lung neutrophilic infiltration after injurious ventilation, with no differences in Il6 or Il10 expression. Microarray analyses revealed a downregulation of Calcb, Hspa1b, and Ccl3, three genes related to tolerance phenomena, in preconditioned animals. Among the previously identified genes, only Ccl3, which encodes the macrophage inflammatory protein 1 alpha (MIP-1α), showed significant differences between intact and preconditioned mice after high-pressure ventilation. In separate, nonconditioned animals, treatment with BX471, a specific blocker of CCR1 (the main receptor for MIP-1α), decreased lung damage and neutrophilic infiltration caused by high-pressure ventilation. We conclude that previous exposure to noninjurious ventilation induces a state of tolerance to VILI. Downregulation of the chemokine gene Ccl3 could be the mechanism responsible for this effect.

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Molecular Mechanisms in Acute Lung Injury

Advances in Pharmacology ◽

10.1016/s1054-3589(08)60940-0 ◽

1993 ◽

pp. 275-292 ◽

Cited By ~ 8

Author(s):

Peter A. Ward ◽

Michael S. Mulligan

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Molecular Mechanisms

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Basic and clinical research progress in acute lung injury/acute respiratory distress syndrome

Infection International ◽

10.2478/ii-2018-0017 ◽

2018 ◽

Vol 7 (2) ◽

pp. 38-43 ◽

Cited By ~ 2

Author(s):

Tong Wang

Keyword(s):

Acute Respiratory Distress Syndrome ◽

Acute Lung Injury ◽

Lung Injury ◽

Respiratory Distress Syndrome ◽

Respiratory Distress ◽

Molecular Mechanisms ◽

Distress Syndrome ◽

Severe Infection ◽

Research Progress ◽

Severe Stage

Abstract Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is an acute progressive respiratory failure caused by severe infection, trauma, shock, poisoning, inhaled harmful gas, acute pancreatitis, and pathological obstetrics. ALI and ARDS demonstrate similar pathophysiological changes. The severe stage of ALI is defined as ARDS. At present, a significant progress has been achieved in the study of the pathogenesis and pathophysiology of ALI/ARDS. Whether or not ALI/ARDS patients can recover depends on the degree of lung injury, extra-pulmonary organ damage, original primary disease of a patient, and adequacy in supportive care. Conservative infusion strategies and protective lung ventilation reduce ARDS disability and mortality. In this study, the pathogenesis of ALI/ARDS, lung injury, molecular mechanisms of lung repair, and conservative infusion strategies and pulmonary protective ventilation are reviewed comprehensively.

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