Animals ; Humans ; MicroRNAs ; Pneumonia ; genetics ; Pulmonary Fibrosis ; genetics

BackgroundIdiopathic pulmonary fibrosis (IPF) is an age-related and progressive interstitial lung disease. Up to 20% of cases of IPF cluster in families, genetic factors contribute significantly to the pathogenesis of the disease. This study aimed to explore the association between rare genetic variants and IPF in Chinese Han families.

MethodsA Han family, comprising three IPF patients and five unaffected their first-degree relatives, and 100 ethnically matched control individuals from North China were enrolled in this study. Peripheral blood was collected, and genomic DNA was extracted. To elucidate if rare genetic variants are associated with the familial IPF, we performed whole-exome sequencing of affected members from a Chinese Han IPF family. Candidate rare variants were then confirmed by Sanger sequencing.

ResultsWe identified a potentially damaging rare variant-a heterozygous mutation c.2146G>A in exon 6 of the gene encoding for telomerase reverse transcriptase (TERT), which results in an amino acid substitution (p.Ala716Thr). We confirmed the missense mutation by Sanger sequencing in all the affected family members but did not detect this mutation in 100 ethnically matched healthy controls. Patients carried this mutation were characterized by the frequently acute exacerbation of IPF phenotype, with poor prognosis. The mean time to death was 2.8 years after diagnosis.

ConclusionUsing next-generation sequencing technology in familial IPF patients, we identified the heterozygous rare variant in TERT gene, and strengthened the importance of genetic variants in telomere-related pathogenesis in Chinese IPF patients.

China ; Female ; Humans ; Idiopathic Pulmonary Fibrosis ; genetics ; Male ; Middle Aged ; Mutation ; Mutation, Missense ; Pulmonary Fibrosis ; Telomerase ; genetics ; Telomere

Humans ; Idiopathic Pulmonary Fibrosis/genetics* ; Lung ; MicroRNAs/genetics* ; RNA, Messenger/genetics*

OBJECTIVETo evaluate the effect of water channel aquaporin 4 (AQP4) on bleomycin-induced lung fibrosis in mice.

METHODSIn wild type and AQP4 gene knockout (AQP4-/-) mice, lung fibrosis was induced by injection of bleomycin (3 mg/kg) into the trachea and saline injection was used as a control. At d3, 7, 14, 28 after bleomycin-treatment, mice were randomly sacrificed in batch and the lung coefficient was determined. Serum levels of TGF-β1 and TNF-α were measured by ELISA and hydroxyproline contents in lung tissue were determined by Alkaline hydrolysis method. H-E staining and Masson's staining were performed to examine the pathological changes of lung tissues after bleomycin-treatment.

RESULTSOn d14 after bleomycin-treatment, the lung coefficients in wild type mice and AQP4-/- mice were 1.9-fold (12.69 ± 6.05 vs 6.80 ± 0.82, q=4.204, P<0.05) and 2.3-fold (14.05 ± 5.82 vs 6.05± 0.58, q=5.172, P<0.01) of that in control, respectively, but no significant difference was found between wild type and AQP4-/- mice in the lung coefficient value (P>0.05). The hydroxyproline contents in the lung increased after bleomycin-treatment; on d28, the lung hydroxyproline contents in wild type and in AQP4-/- mice were 1.55-fold (0.85 ± 0.22 g/mg vs 0.55 ± 0.14 μg/mg, q=4.313, P<0.05) and 1.4-fold (0.84 ± 0.13 μg/mg vs 0.60 ± 0.14μg/mg, q=4.595，P<0.05) of that in control, respectively, but no significant difference was noticed between wild type and AQP4-/- mice in lung hydroxyproline contents. There was a tendency that serum TGF-β1 and TNF-α levels increased in bleomycin-treated mice, but no significant difference was found between wild type and AQP4-/- mice. AQP4-knockout showed no effects on pathological changes of lung tissues with H-E staining and Masson's staining in mice with bleomycin-induced lung fibrosis.

CONCLUSIONAQP4 might not be involved in bleomycin-induced lung fibrosis in mice.

Animals ; Aquaporin 4 ; genetics ; Bleomycin ; toxicity ; Male ; Mice ; Mice, Knockout ; Pulmonary Fibrosis ; chemically induced ; genetics

Humans ; Polymorphism, Genetic ; Pulmonary Fibrosis ; genetics ; physiopathology ; Transforming Growth Factor beta ; genetics ; physiology

Genetic Predisposition to Disease ; Humans ; Pneumoconiosis ; complications ; genetics ; Pulmonary Fibrosis ; etiology ; genetics

Biomarkers ; Humans ; Idiopathic Pulmonary Fibrosis/genetics* ; MicroRNAs/metabolism* ; Sjogren's Syndrome/genetics*

OBJECTIVETo explore the mechanism of moxibustion arresting the pulmonary fibrosis and provide experimental basis for prevention and treatment of pulmonary fibrosis with acupuncture and moxibustion.

METHODSOne hundred and forty SD rats were randomly assigned to 4 groups: a blank group, a model group, a moxibustion group and a prednisone group, 35 rats in each group. The 3 groups expect the blank group were injected with bleomycin via trachea to induce experimental pulmonary fibrosis model, and 7 days after modeling, they were treated with moxibustion at bilateral Feishu (BL 13) and Gaohuang (BL 43), 3 cones each point, once each day, 10 days constituting one therapeutic course with an interval of one day between courses. After 3 courses, all rats were killed and expressions of TGF-beta1mRNA were detected with PCR method.

RESULTSThe content of TGF-beta1mRNA in the pulmonary tissue in the moxibustion group and the prednisone group was significantly lower than the model group (P < 0.01), and there was no significant difference between the moxibustion group and the prednisone group (P > 0. 05).

CONCLUSIONBoth moxibustion at Feishu (BL 13) and Gaohuang (BL 43), and prednisone treatment can significantly suppress the expression of TGF-beta1mRNA in the pulmonary tissue in the rat of bleomycin-induced pulmonary fibrosis.

Animals ; Bleomycin ; Humans ; Moxibustion ; Pulmonary Fibrosis ; Rats, Sprague-Dawley ; Transforming Growth Factor beta1 ; genetics

There have been recent extensive studies and rapid advancement on the pathogenesis underlying idiopathic pulmonary fibrosis (IPF), and intricate pathogenesis of IPF has been suggested. The purpose of this study was to clarify the logical relationship between these mechanisms. An extensive search was undertaken of the PubMed using the following keywords: "etiology," "pathogenesis," "alveolar epithelial cell (AEC)," "fibroblast," "lymphocyte," "macrophage," "epigenomics," "histone," acetylation," "methylation," "endoplasmic reticulum stress," "mitochondrial dysfunction," "telomerase," "proteases," "plasminogen," "epithelial-mesenchymal transition," "oxidative stress," "inflammation," "apoptosis," and "idiopathic pulmonary fibrosis." This search covered relevant research articles published up to April 30, 2020. Original articles, reviews, and other articles were searched and reviewed for content; 240 highly relevant studies were obtained after screening. IPF is likely the result of complex interactions between environmental, genetic, and epigenetic factors: environmental exposures affect epigenetic marks; epigenetic processes translate environmental exposures into the regulation of chromatin; epigenetic processes shape gene expression profiles; in turn, an individual's genetic background determines epigenetic marks; finally, these genetic and epigenetic factors act in concert to dysregulate gene expression in IPF lung tissue. The pathogenesis of IPF involves various imbalances including endoplasmic reticulum, telomere length homeostasis, mitochondrial dysfunction, oxidant/antioxidant imbalance, Th1/Th2 imbalance, M1-M2 polarization of macrophages, protease/antiprotease imbalance, and plasminogen activation/inhibition imbalance. These affect each other, promote each other, and ultimately promote AEC/fibroblast apoptosis imbalance directly or indirectly. Excessive AEC apoptosis and impaired apoptosis of fibroblasts contribute to fibrosis. IPF is likely the result of complex interactions between environmental, genetic, and epigenetic factors. The pathogenesis of IPF involves various imbalances centered on AEC/fibroblast apoptosis imbalance.
Alveolar Epithelial Cells ; Apoptosis ; Endoplasmic Reticulum Stress ; Fibroblasts ; Humans ; Idiopathic Pulmonary Fibrosis/genetics*

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is an idiopathic chronic, progressive interstitial lung disease with a diagnosed median survival of 3-5 years. IPF is associated with an increased risk of lung cancer. Therefore, exploring the shared pathogenic genes and molecular pathways between IPF and lung adenocarcinoma (LUAD) holds significant importance for the development of novel therapeutic approaches and personalized precision treatment strategies for IPF combined with lung cancer. METHODS: Bioinformatics analysis was conducted using publicly available gene expression datasets of IPF and LUAD from the Gene Expression Omnibus (GEO) database. Weighted gene co-expression network analysis was employed to identify common genes involved in the progression of both diseases, followed by functional enrichment analysis. Subsequently, additional datasets were used to pinpoint the core shared genes between the two diseases. The relationship between core shared genes and prognosis, as well as their expression patterns, clinical relevance, genetic characteristics, and immune-related functions in LUAD, were analyzed using The Cancer Genome Atlas (TCGA) database and single-cell RNA sequencing datasets. Finally, potential therapeutic drugs related to the identified genes were screened through drug databases. RESULTS: A total of 529 shared genes between IPF and LUAD were identified. Among them, SULF1 emerged as a core shared gene associated with poor prognosis. It exhibited significantly elevated expression levels in LUAD tissues, concomitant with high mutation rates, genomic heterogeneity, and an immunosuppressive microenvironment. Subsequent single-cell RNA-seq analysis revealed that the high expression of SULF1 primarily originated from tumor-associated fibroblasts. This study further demonstrated an association between SULF1 expression and tumor drug sensitivity, and it identified potential small-molecule drugs targeting SULF1 highly expressed fibroblasts. CONCLUSIONS This study identified a set of shared molecular pathways and core genes between IPF and LUAD. Notably, SULF1 may serve as a potential immune-related biomarker and therapeutic target for both diseases.
Humans ; Lung Neoplasms/genetics* ; Adenocarcinoma of Lung/genetics* ; Idiopathic Pulmonary Fibrosis/genetics* ; Adenocarcinoma ; Cancer-Associated Fibroblasts ; Prognosis ; Tumor Microenvironment ; Sulfotransferases