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Smad5 (small mothers against decapentaplegic 5) protein is a receptor-regulated member of the Smad family proteins, mainly participating in the bone morphogenetic protein (BMP) signaling pathway in its phosphorylated form. This article will provide a detailed review of Smad5, focusing on its gene characteristics, protein structure, and subcellular localization properties. We will also explore the related signaling pathways and the mechanisms of Smad5 in respiratory diseases, including chronic obstructive pulmonary disease (COPD), bronchial asthma, pulmonary arterial hypertension(PAH), lung cancer, and idiopathic pulmonary fibrosis (IPF). Additionally, the review will cover aspects such as proliferation, differentiation, apoptosis, anti-fibrosis, and mitochondrial function metabolism. In addition, the review will cover aspects of proliferation, differentiation, apoptosis, anti-fibrosis and functional mitochondrial metabolism related to the above topics. Numerous studies suggest that Smad5 may play a unique and important role in the pathogenesis of respiratory system diseases. However, in previous research, Smad5 was mainly used to broadly determine the activation of the BMP signaling pathway, and its own function has not been given much attention. It is worth noting that Smad5 has distinct nuclear-cytoplasmic distribution characteristics different from Smad1 and Smad8. It can undergo significant nuclear-cytoplasmic shuttling when intracellular pH (pHi) changes, playing important roles in both the classical BMP signaling pathway and non-BMP signaling pathways. Given that Smad5 can move intracellularly in response to changes in physicochemical properties, its cellular localization may play a crucial role in the development of respiratory diseases. This article will explore the possibility that its distribution characteristics may be an important factor that is easily overlooked and not adequately considered in disease research., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: All authors read and approved the final version of the manuscript. Otherwise consent not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Respiratory diseases in children are common health problems that significantly impact their quality of life and health status, and this has its own unique challenges compared to adults. A growing body of research has focused on epigenetic mechanisms that relate with the development of various diseases, such as pediatric respiratory diseases. Noncoding RNAs (ncRNAs), especially long noncoding RNAs, microRNA, and circular RNA, are reported to play a regulatory role in pediatric respiratory diseases whose mutations or aberrant expressions are strongly associated with the development of these diseases. In this review, we mainly discussed the functions of these three ncRNAs in pediatric respiratory diseases.

Observational studies and clinical trials have suggested the relationship between the gut microbiome and respiratory diseases, but the causality between them remains unclear. Firstly, we selected eight respiratory diseases Genome-wide association study (GWAS) datasets mainly from the FinnGen collaboration as outcomes. The exposure was based on GWAS statistics about the gut microbiome, sourced from the MiBioGen consortium, including gut microbial taxa. The causal link between the gut microbiome and respiratory illnesses was then estimated using a Two-sample Mendelian randomization (MR) analysis, including the inverse-variance weighted (IVW), weighted median, MR-Egger, simple mode, and weighted mode. To ensure reliability, F-statistics and sensitivity tests were conducted. Furthermore, we performed a reverse MR analysis of the pre-Mendelian positive findings to possible reverse causality. For the 196 gut microbe taxa, the IVW analysis suggested 88 potential associations with eight clinically prevalent respiratory diseases. Among them, 30 causal associations were found in more than one MR method. Multiple statistical corrections have confirmed three causal associations: genus Holdemanella was a risk factor for chronic obstructive pulmonary disease (COPD) (P = 1.3 × 10 -4 , OR = 1.18), family FamilyXIII was a protective factor for COPD (P = 1.3 × 10 -3 , OR = 0.75), and genus Oxalobacter was a risk factor for asthma (P = 2.1 × 10 -4 , OR = 1.09). Our MR analysis results indicate that there would be a causal relationship between the gut microbiome and respiratory diseases, contributing to the gut-lung axis. This finding offers new insights into the gut microbiome's roles in respiratory diseases' clinical prevention, pathogenesis, and improvement of clinical symptoms. Further randomized controlled trials are necessary to clarify the protective effect of probiotics and fecal microbial transplantation on respiratory health., (© 2024. The Author(s).)

Background: Sarcopenia (SP) is an aging-related loss of muscle mass and function, affecting the respiratory system. However, the causality of the association between sarcopenia on lung diseases remains elusive., Methods: The bidirectional univariate Mendelian randomization (UVMR), multivariate MR (MVMR) analysis, and mediation MR were utilized to systematically investigate the genetic causal relationship of SP and 11 respiratory diseases. Independent genomic variants related to sarcopenia or respiratory diseases were identified as instrumental variables (IVs), and the summary level data of genome-wide associated studies (GWAS) were obtained from the UK biobank and FinnGen. MVMR analysis was conducted to explore the mediation effects of body mass index (BMI), Alcohol Use Disorders Identification Test (AUDIT), smoking, education attainment (EA), physical activity, and Type 2 Diabetes Mellitus (T2DM)., Results: Forward UVMR analysis based on the primary method revealed that pneumoconiosis was associated with a higher risk of appendicular lean mass (ALM) (OR = 1.01, p = 0.03), and BMI (10.65%), smoking (10.65%), and physical activity (17.70%) had a mediating role in the effect of pneumoconiosis on ALM. In reverse MR analysis, we found that genetically predicted ALM was significantly associated with an increased risk of pulmonary embolism (PE) (OR = 1.24, p = 7.21E-05). Chronic obstructive pulmonary disease (COPD) (OR = 0.98, p = 0.002) and sarcoidosis (OR = 1.01, p = 0.004) were identified to increase the loss of left-hand grip strength (HGS). Conversely, the increase in left- HGS presented a protective effect on chronic bronchitis (CB) (OR = 0.35, p = 0.03), (OR = 0.80, p = 0.02), and asthma (OR = 0.78, p = 0.04). Similarly, the loss of the right-HGS elevated the risk of low respiratory tract infection (LRTI) (OR = 0.97, p = 0.02) and bronchiectasis (OR = 1.01, p = 0.03), which is also an independent protective factor for LRTI and asthma. In the aspects of low HGS, the risk of LRTI was increased after MVMR analysis, and the risk of sarcoidosis and pneumoconiosis was elevated in the reverse analysis. Lastly, asthma was found to be related to the loss of the usual walking pace, and the reverse MR analysis suggested a causal relationship between the usual walking pace and LRTI (OR = 0.32, p = 2.79 × 10- 5 ), asthma (OR = 0.24, p = 2.09 × 10- 6 ), COPD (OR = 0.22, p = 6.64 × 10- 4 ), and PE(OR = 0.35, p = 0.03)., Conclusions: This data-driven MR analysis revealed SP was bidirectional causally associated with lung diseases, providing genetic evidence for further mechanistic and clinical studies to understand the crosstalk between SP and lung diseases., (© 2024. The Author(s).)

Background: PM 2.5 has been associated with various adverse health effects, particularly affecting lung function and chronic respiratory diseases. However, the genetic causality relationship between PM 2.5 exposure and lung function as well as chronic respiratory diseases remains poorly understood., Method: We conducted a two-sample Mendelian randomization analysis to investigate the causal impact of PM 2.5 on lung function and chronic respiratory diseases. Instrumental variables were carefully selected, with significance thresholds (P < 5 × 10 - 8 ), and linkage disequilibrium with an r 2 value below 0.001. Additionally, SNPs with an F-statistic exceeding 10 were included to mitigate potential bias stemming from weak instrumental variables. The primary analytical approach employed the Inverse Variance Weighted method, supplemented by the Weighted Median, MR-Egger, Simple Model, and Weighted Model. Furthermore, pleiotropy and heterogeneity were evaluated through the MR-Egger intercept test and Cochrane's Q test, with a sensitivity analysis conducted using the leave-one-out method., Results: Eight SNPs significantly associated with PM 2.5 exposure were identified as Instrumental variables. Mendelian randomization analysis revealed a significant causal association between PM 2.5 exposure and lung function (FEV), with an OR of 0.7284 (95% CI: 0.5799-0.9150). Similarly, PM 2.5 exposure demonstrated a substantial causal effect on asthma, with an OR of 1.5280 (95% CI: 1.0470-2.2299). However, no causal association was observed between PM 2.5 exposure and chronic obstructive pulmonary disease, with an OR of 1.5176 (95% CI: 0.8294-2.7768)., Conclusion: These findings emphasize the necessity for continued research efforts in environmental health to develop effective strategies for the prevention and management of chronic respiratory diseases., (© 2024. The Author(s) under exclusive licence to International Society of Biometeorology.)

Background: Current knowledge suggests that the gene region containing MUC5B and TOLLIP plays a role in airway defence and airway inflammation, and hence respiratory disease. It is also known that exposure to air pollution increases susceptibility to respiratory disease. We aimed to study whether the effect of air pollutants on the immune response and respiratory symptoms in infants may be modified by polymorphisms in MUC5B and TOLLIP genes., Methods: 359 healthy term infants from the prospective Basel-Bern Infant Lung Development (BILD) birth cohort were included in the study. The main outcome was the score of weekly assessed respiratory symptoms in the first year of life. Using the candidate gene approach, we selected 10 single nucleotide polymorphisms (SNPs) from the MUC5B and TOLLIP regions. Nitrogen dioxide (NO 2 ) and particulate matter ≤10 μm in aerodynamic diameter (PM 10 ) exposure was estimated on a weekly basis. We used generalised additive mixed models adjusted for known covariates. To validate our results in vitro, cells from a lung epithelial cell line were downregulated in TOLLIP expression and exposed to diesel particulate matter (DPM) and polyinosinic-polycytidylic acid., Results: Significant interaction was observed between modelled air pollution (weekly NO 2 exposure) and 5 SNPs within MUC5B and TOLLIP genes regarding respiratory symptoms as outcome: E.g., infants carrying minor alleles of rs5744034, rs3793965 and rs3750920 (all TOLLIP) had an increased risk of respiratory symptoms with increasing NO 2 exposure. In vitro experiments showed that cells downregulated for TOLLIP react differently to environmental pollutant exposure with DPM and viral stimulation., Conclusion: Our findings suggest that the effect of air pollution on respiratory symptoms in infancy may be influenced by the genotype of specific SNPs from the MUC5B and TOLLIP regions. For validation of the findings, we provided in vitro evidence for the interaction of TOLLIP with air pollution., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Urs Frey reports financial support was provided by Swiss National Science Foundation. Celine Ruettimann reports a relationship with Freie Akademische Gesellschaft Basel that includes: funding grants. Philipp Latzin reports a relationship with Vertex that includes: board membership, funding grants, and speaking and lecture fees. Philipp Latzin reports a relationship with Vifor Pharma Switzerland SA that includes: speaking and lecture fees. Philipp Latzin reports a relationship with OM Pharma Ltd that includes: board membership, funding grants, and speaking and lecture fees. Philipp Latzin reports a relationship with Polyphor Ltd that includes: board membership. Philipp Latzin reports a relationship with Santhera Pharmaceuticals Schweiz AG that includes: board membership. Philipp Latzin reports a relationship with Allecra Therapeutics that includes: board membership. Philipp Latzin reports a relationship with Sanofi that includes: board membership. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Interest in dairy cow health continues to grow as we better understand health's relationship with production potential and animal welfare. Over the past decade, efforts have been made to incorporate health traits into national genetic evaluations. However, they have focused on the mature cow, with calf health largely being neglected. Diarrhoea and respiratory disease comprise the main illnesses with regard to calf health. Conventional methods to control calf disease involve early separation of calves from the dam and housing calves individually. However, public concern regarding these methods, and growing evidence that these methods may negatively impact calf development, mean the dairy industry may move away from these practices. Genetic selection may be a promising tool to address these major disease issues. In this review, we examined current literature for enhancing calf health through genetics and discussed alternative approaches to improve calf health via the use of epidemiological modelling approaches, and the potential of indirectly selecting for improved calf health through improving colostrum quality. Heritability estimates on the observed scale for diarrhoea ranged from 0.03 to 0.20, while for respiratory disease, estimates ranged from 0.02 to 0.24. The breadth in these ranges is due, at least in part, to differences in disease prevalence, population structure, data editing and models, as well as data collection practices, which should be all considered when comparing literature values. Incorporation of epidemiological theory into quantitative genetics provides an opportunity to better determine the level of genetic variation in disease traits, as it accounts for disease transmission among contemporaries. Colostrum intake is a major determinant of whether a calf develops either respiratory disease or diarrhoea. Colostrum traits have the advantage of being measured and reported on a continuous scale, which removes the issues classically associated with binary disease traits. Overall, genetic selection for improved calf health is feasible. However, to ensure the maximum response, first steps by any industry members should focus efforts on standardising recording practices and encouragement of uploading information to genetic evaluation centres through herd management software, as high-quality phenotypes are the backbone of any successful breeding programme., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Dysregulation of inflammation can lead to multiple chronic respiratory diseases, such as chronic obstructive pulmonary disease (COPD) and asthma. Interleukin-6 (IL6) is crucial in regulating the inflammatory cascade, but the causal link between IL6 signaling downregulation and respiratory diseases risk is unclear. This study uses Mendelian randomization to examine the effects of IL6R blockade on respiratory diseases. Analyzing data from 522,681 Europeans, 26 genetic variants were obtained to mimic IL6R inhibition. Our findings show that IL6R blockade significantly reduces the risk of COPD (OR = 0.71, 95% CI = 0.60-9.84) and asthma (OR = 0.82, 95% CI = 0.74-0.90), with protective trends for bronchitis, pulmonary embolism, and lung cancer. Results were consistent across methods, with no significant heterogeneity or pleiotropy. These insights suggest IL6R downregulation as a potential therapeutic target for respiratory diseases, meriting further clinical investigation., (© 2024. The Author(s).)

Respiratory disorders are among the conditions that affect the respiratory system. The healthcare sector faces challenges due to the emergence of drug resistance to prescribed medications for these illnesses. However, there is a technology called CRISPR/Cas9, which uses RNA to guide DNA targeting. This technology has revolutionized our ability to manipulate and visualize the genome, leading to advancements in research and treatment development. It can effectively reverse epigenetic alterations that contribute to drug resistance. Some studies focused on health have shown that targeting genes using CRISPR/Cas9 can be challenging when it comes to reducing drug resistance in patients with respiratory disorders. Nevertheless, it is important to acknowledge the limitations of this technology, such as off-target effects, immune system reactions to Cas9, and challenges associated with delivery methods. Despite these limitations, this review aims to provide knowledge about CRISPR/Cas9 genome editing tools and explore how they can help overcome resistance in patients with respiratory disorders. Additionally, this study discusses concerns related to applications of CRISPR and provides an overview of successful clinical trial studies., (© 2024. The Author(s).)

Objective: This study aims to explore the common genetic basis between respiratory diseases and to identify shared molecular and biological mechanisms., Methods: This genome-wide pleiotropic association study uses multiple statistical methods to systematically analyse the shared genetic basis between five respiratory diseases (asthma, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, lung cancer and snoring) using the largest publicly available genome wide association studies summary statistics. The missions of this study are to evaluate global and local genetic correlations, to identify pleiotropic loci, to elucidate biological pathways at the multiomics level and to explore causal relationships between respiratory diseases. Data were collected from 27 November 2022 to 30 March 2023 and analysed from 14 April 2023 to 13 July 2023., Main Outcomes and Measures: The primary outcomes are shared genetic loci, pleiotropic genes, biological pathways and estimates of genetic correlations and causal effects., Results: Significant genetic correlations were found for 10 paired traits in 5 respiratory diseases. Cross-Phenotype Association identified 12 400 significant potential pleiotropic single-nucleotide polymorphism at 156 independent pleiotropic loci. In addition, multitrait colocalisation analysis identified 15 colocalised loci and a subset of colocalised traits. Gene-based analyses identified 432 potential pleiotropic genes and were further validated at the transcriptome and protein levels. Both pathway enrichment and single-cell enrichment analyses supported the role of the immune system in respiratory diseases. Additionally, five pairs of respiratory diseases have a causal relationship., Conclusions and Relevance: This study reveals the common genetic basis and pleiotropic genes among respiratory diseases. It provides strong evidence for further therapeutic strategies and risk prediction for the phenomenon of respiratory disease comorbidity., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Farm exposures in early life reduce the risks for childhood allergic diseases and asthma. There is less information about how farm exposures relate to respiratory illnesses and mucosal immune development., Objective: We hypothesized that children raised in farm environments have a lower incidence of respiratory illnesses over the first 2 years of life than nonfarm children. We also analyzed whether farm exposures or respiratory illnesses were related to patterns of nasal cell gene expression., Methods: The Wisconsin Infant Study Cohort included farm (n = 156) and nonfarm (n = 155) families with children followed to age 2 years. Parents reported prenatal farm and other environmental exposures. Illness frequency and severity were assessed using illness diaries and periodic surveys. Nasopharyngeal cell gene expression in a subset of 64 children at age 2 years was compared to farm exposure and respiratory illness history., Results: Farm versus nonfarm children had nominally lower rates of respiratory illnesses (rate ratio 0.82 [95% CI, 0.69, 0.97]) with a stepwise reduction in illness rates in children exposed to 0, 1, or ≥2 animal species, but these trends were nonsignificant in a multivariable model. Farm exposures and preceding respiratory illnesses were positively related to nasal cell gene signatures for mononuclear cells and innate and antimicrobial responses., Conclusions: Maternal and infant exposure to farms and farm animals was associated with nonsignificant trends for reduced respiratory illnesses. Nasal cell gene expression in a subset of children suggests that farm exposures and respiratory illnesses in early life are associated with distinct patterns of mucosal immune expression., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

MicroRNAs (miRNAs) are short, non-coding single-stranded RNA molecules approximately 22 nucleotides in length, intricately involved in post-transcriptional gene expression regulation. Over recent years, researchers have focused keenly on miRNAs, delving into their mechanisms in various diseases such as cancers. Among these, miR-26a emerges as a pivotal player in respiratory ailments such as pneumonia, idiopathic pulmonary fibrosis, lung cancer, asthma, and chronic obstructive pulmonary disease. Studies have underscored the significance of miR-26a in the pathogenesis and progression of respiratory diseases, positioning it as a promising therapeutic target. Nevertheless, several challenges persist in devising medical strategies for clinical trials involving miR-26a. In this review, we summarize the regulatory role and significance of miR-26a in respiratory diseases, and we analyze and elucidate the challenges related to miR-26a druggability, encompassing issues such as the efficiency of miR-26a, delivery, RNA modification, off-target effects, and the envisioned therapeutic potential of miR-26a in clinical settings., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Shrine et al. 1 conducted the largest multi-ancestry genome-wide meta-analysis of lung function and identified 1,020 signals associated with lung function. These provide novel insights into the genetic underpins of lung function and may inform better clinical management of respiratory disorders., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023. Published by Elsevier Inc.)

Macrophages play an essential role in maintaining the normal function of the innate and adaptive immune responses during host defence. Macrophages acquire diverse functional phenotypes in response to various microenvironmental stimuli, and are mainly classified into classically activated macrophages (M1) and alternatively activated macrophages (M2). Macrophage polarization participates in the inflammatory, fibrotic, and oncogenic processes of diverse respiratory diseases by changing phenotype and function. In recent decades, with the advent of broad-range profiling methods such as microarrays and next-generation sequencing, the discovery of RNA transcripts that do not encode proteins termed "noncoding RNAs (ncRNAs)" has become more easily accessible. As one major member of the regulatory ncRNA family, long noncoding RNAs (lncRNAs, transcripts >200 nucleotides) participate in multiple pathophysiological processes, including cell proliferation, differentiation, and apoptosis, and vary with different stimulants and cell types. Emerging evidence suggests that lncRNAs account for the regulation of macrophage polarization and subsequent effects on respiratory diseases. In this review, we summarize the current published literature from the PubMed database concerning lncRNAs relevant to macrophage polarization and the underlying molecular mechanisms during the occurrence and development of respiratory diseases. These differentially expressed lncRNAs are expected to be biomarkers and targets for the therapeutic regulation of macrophage polarization during disease development., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Qiao, Ding, Wu, Zhang, Yin, Wang, Wang and Kang.)

Modern society grew rapidly over the last few decades and this led to an alarming increase in air pollutants and a worsening of the human health, especially in relation to the respiratory system. Indeed, chronic respiratory diseases were the third main cause of death in 2017, with over 3 million of deaths. Furthermore, the pollution has considerable consequences both for burden medical expenses and environmental. However, the mechanisms linking pollutants to the onset of these diseases remain unclear. Thus, in this study we addressed this problem through the United Kingdom BioBank database, analyzing 170 genome-wide association studies (103 related to respiratory diseases and 67 related to pollutants). We analyzed the genetic correlations and causal relationships of these traits, leveraging the summary statistics and bioinformatics packages such as Linkage Disequilibrium Score Regression and Latent Causal Variable. We obtained 158 significant genetic correlations and subsequently we analyzed them through the Latent Causal Variable analysis, obtaining 20 significant causal relationships. The most significant were between "Workplace full of chemicals or other fumes: Sometimes" and "Condition that has ever been diagnosed by a doctor: Asthma" and between "Workplace very dusty: Sometimes" and "Condition that has ever been diagnosed by a doctor: Emphysema or chronic bronchitis". Finally, we identified single nucleotide polymorphisms independently associated with sveral pollutants to analyze the genes and pathways that could be involved in the onset of the aforementioned respiratory system disorders and that could be useful clinical target. This study highlighted how crucial are the air condition of the working environments and the type of transport used in the onset of respiratory-related morbidity. Based on that, we also suggested some interventions, in order to improve quality life and develop new and eco-friendly society and life style, such as improving indoor air circulation, the use of public transport and urban reforestation., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 D'Antona et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Bovine respiratory disease (BRD), the leading disease complex in beef cattle production systems, remains highly elusive regarding diagnostics and disease prediction. Previous research has employed cellular and molecular techniques to describe hematological and gene expression variation that coincides with BRD development. Here, we utilized weighted gene co-expression network analysis (WGCNA) to leverage total gene expression patterns from cattle at arrival and generate hematological and clinical trait associations to describe mechanisms that may predict BRD development. Gene expression counts of previously published RNA-Seq data from 23 cattle (2017; n = 11 Healthy, n = 12 BRD) were used to construct gene co-expression modules and correlation patterns with complete blood count (CBC) and clinical datasets. Modules were further evaluated for cross-populational preservation of expression with RNA-Seq data from 24 cattle in an independent population (2019; n = 12 Healthy, n = 12 BRD). Genes within well-preserved modules were subject to functional enrichment analysis for significant Gene Ontology terms and pathways. Genes which possessed high module membership and association with BRD development, regardless of module preservation ("hub genes"), were utilized for protein-protein physical interaction network and clustering analyses. Five well-preserved modules of co-expressed genes were identified. One module ("steelblue"), involved in alpha-beta T-cell complexes and Th2-type immunity, possessed significant correlation with increased erythrocytes, platelets, and BRD development. One module ("purple"), involved in mitochondrial metabolism and rRNA maturation, possessed significant correlation with increased eosinophils, fecal egg count per gram, and weight gain over time. Fifty-two interacting hub genes, stratified into 11 clusters, may possess transient function involved in BRD development not previously described in literature. This study identifies co-expressed genes and coordinated mechanisms associated with BRD, which necessitates further investigation in BRD-prediction research., Competing Interests: The authors have declared that no competing interests exist.

Objective: This study aimed to investigate the prevalence and clinical characteristics of monogenic disease in paediatric patients with a predominant respiratory phenotype., Methods: Exome sequencing was performed in a cohort of 971 children with a predominant respiratory phenotype and suspected genetic aetiology. A total of 140 positive cases were divided into subgroups based on recruitment age and the primary biological system(s) involved., Results: There were 140 (14.4%) patients with a positive molecular diagnosis, and their primary clinical manifestations were respiratory distress (12.9%, 18 of 140), respiratory failure (12.9%, 18 of 140) and recurrent/persistent lower respiratory infections (66.4%, 93 of 140). Primary immunodeficiency (49.3%), multisystem malformations/syndromes (17.9%), and genetic lung disease (16.4%) were the three most common genetic causes in the cohort, and they varied among the age subgroups. A total of 72 (51.4%) patients had changes in medical management strategies after genetic diagnosis, and the rate in those with genetic lung disease (82.6%, 19 of 23) was far higher than that in patients with genetic disease with lung involvement (45.3%, 53 of 117) (p=0.001)., Conclusion: Our findings demonstrate that exome sequencing is a valuable diagnostic tool for monogenic diseases in children with a predominant respiratory phenotype, and the genetic spectrum varies with age. Taken together, genetic diagnoses provide invaluable clinical and prognostic information that may also facilitate the development of precision medicine for paediatric patients., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Over the past decade, "omics" approaches have advanced our understanding of the molecular programming of the airways in humans. Several studies have identified potential molecular mechanisms that contribute to early life epigenetic reprogramming, including DNA methylation, histone modifications, microRNAs, and the homeostasis of the respiratory mucosa (epithelial function and microbiota). Current evidence supports the notion that early infancy is characterized by heightened susceptibility to airway genetic reprogramming in response to the first exposures in life, some of which can have life-long consequences. Here, we summarize and analyze the latest insights from studies that support a novel epigenetic paradigm centered on human maturational and developmental programs including three cardinal elements: genes, environment, and developmental timing. The combination of these factors is likely responsible for the functional trajectory of the respiratory system at the molecular, functional, and clinical levels., (© 2021 Wiley Periodicals LLC.)

The transient receptor potential melastatin subtype 8 (TRPM8) is a cold sensor in humans, activated by low temperatures (>10, <28 °C), but also a polymodal ion channel, stimulated by voltage, pressure, cooling compounds (menthol, icilin), and hyperosmolarity. An increased number of experimental results indicate the implication of TRPM8 channels in cold thermal transduction and pain detection, transmission, and maintenance in different tissues and organs. These channels also have a repercussion on different kinds of life-threatening tumors and other pathologies, which include urinary and respiratory tract dysfunctions, dry eye disease, and obesity. This compendium firstly covers newly described papers on the expression of TRPM8 channels and their correlation with pathological states. An overview on the structural knowledge, after cryo-electron microscopy success in solving different TRPM8 structures, as well as some insights obtained from mutagenesis studies, will follow. Most recently described families of TRPM8 modulators are also covered, along with a section of molecules that have reached clinical trials. To finalize, authors provide an outline of the potential prospects in the TRPM8 field.

Identification of a quantitative trait locus (QTL) related to a chronic respiratory disease such as Mycoplasmal pneumonia of swine (MPS) and immune-related traits is important for the genetic improvement of disease resistance in pigs. The objective of this study was to detect a novel QTL for a total of 22 production, respiratory disease, and immune-related traits in Landrace pigs. A total of 874 Landrace purebred pigs, which were selected based on MPS resistance, were genotyped using the Illumina PorcineSNP60 BeadChip. We performed single nucleotide polymorphism (SNP)-based and haplotype-based genome-wide association studies (GWAS) to detect a novel QTL and to evaluate the possibility of a pleiotropic QTL for these traits. SNP-based GWAS detected a total of six significant regions in backfat thickness, ratio of granular leucocytes to lymphatic cells, plasma concentration of cortisol at different ages, and complement alternative pathway activity in serum. The significant region detected by haplotype-based GWAS was overlapped across the region detected by SNP-based GWAS. Most of these detected QTL regions were novel regions with some candidate genes located in them. With regard to a pleiotropic QTL among traits, only three of these detected QTL regions overlapped among traits, and many detected regions independently affected the traits., (© 2021. The Author(s).)

Pulmonary delivery of small interfering RNA (siRNA) is a promising therapeutic strategy for treating various respiratory diseases but an effective carrier for the delivery of siRNA into the cells of the lungs and a robust gene-silencing effect is still lacking. Previously, we reported that the KL4 peptide, a synthetic cationic peptide with a repeating KLLLL sequence, can mediate effective siRNA transfection in lung epithelial cells but its high hydrophobic leucine content, and hence poor water solubility, limits its application as a delivery vector. Here, we show that the covalent attachment of monodisperse poly(ethylene glycol) (PEG) improves the solubility of KL4 and the uptake of its complex with siRNA into lung epithelial cells, such that very robust silencing is produced. All PEGylated KL4 peptides, with PEG length varying between 6 and 24 monomers, could bind and form nanosized complexes with siRNA, but the interaction between siRNA and peptides became weaker as the PEG chain length increased. All PEGylated KL4 peptides exhibited satisfactory siRNA transfection efficiency on three human lung epithelial cell lines, including A549 cells, Calu-3 cells, and BEAS-2B cells. The PEG 12 KL4 peptide, which contains 12 monomers of PEG, was optimal for siRNA delivery and also demonstrated a low risk of inflammatory response and toxicity in vivo following pulmonary administration.

Recent advances in culture-independent microbiological analyses have greatly expanded our understanding of the diversity of unculturable microbes. However, human pathogenic bacteria differing significantly from known taxa have rarely been discovered. Here, we present the complete genome sequence of an uncultured bacterium detected in human respiratory tract named IOLA, which was determined by developing a protocol to selectively amplify extremely AT-rich genomes. The IOLA genome is 303,838 bp in size with a 20.7% GC content, making it the smallest and most AT-rich genome among known human-associated bacterial genomes to our best knowledge and comparable to those of insect endosymbionts. While IOLA belongs to order Rickettsiales (mostly intracellular parasites), the gene content suggests an epicellular parasitic lifestyle. Surveillance of clinical samples provides evidence that IOLA can be predominantly detected in patients with respiratory bacterial infections and can persist for at least 15 months in the respiratory tract, suggesting that IOLA is a human respiratory tract-associated bacterium.

Aspirin-exacerbated respiratory disease (AERD) is characterized by immune cells dysfunction. This study aimed to investigate the molecular mechanisms involved in AERD pathogenesis. Relevant literatures were identified by a PubMed search (2005-2019) of english language papers using the terms "Aspirin-exacerbated respiratory disease", "Allergic inflammation", "molecular mechanism" and "mutation". According to the significant role of inflammation in AERD development, ILC-2 is known as the most important cell in disease progression. ILC-2 produces cytokines that induce allergic reactions and also cause lipid mediators production, which activates mast cells and basophils, ultimately. Finally, Monoclonal antibody and Aspirin desensitization in patients can be a useful treatment strategy for prevention and treatment.

Equine herpesvirus-1 is the cause of respiratory disease, abortion, and equine herpesvirus myeloencephalopathy (EHM) in horses worldwide. EHM affects as many as 14% of infected horses and a cell-associated viremia is thought to be central for EHM pathogenesis. While EHM is infrequent in younger horses, up to 70% of aged horses develop EHM. The aging immune system likely contributes to EHM pathogenesis; however, little is known about the host factors associated with clinical EHM. Here, we used the "old mare model" to induce EHM following EHV-1 infection. Peripheral blood mononuclear cells (PBMCs) of horses prior to infection and during viremia were collected and RNA sequencing with differential gene expression was used to compare the transcriptome of horses that did (EHM group) and did not (non-EHM group) develop clinical EHM. Interestingly, horses exhibiting EHM did not show respiratory disease, while non-EHM horses showed significant respiratory disease starting on day 2 post infection. Multiple immune pathways differed in EHM horses in response to EHV-1. These included an upregulation of IL-6 gene expression, a dysregulation of T-cell activation through AP-1 and responses skewed towards a T-helper 2 phenotype. Further, a dysregulation of coagulation and an upregulation of elements in the progesterone response were observed in EHM horses.

Objective: Asthma is an inflammatory airway disease affecting most of the population in the world. The current medication for asthma relieves airway inflammation but it has serious adverse effects. Biochanin A (BCA), a phytoestrogen, is an active component present in red clover, alfalfa, soy having anti-oxidant and anti-inflammatory properties. BCA was identified as a natural activator of peroxisome proliferator-activated receptor-gamma (PPARγ)., Methods: The study aims to evaluate the effects of BCA in ovalbumin (OVA)-induced murine model of asthma and to study the role of PPARγ., Results: We found that BCA administration reduced the severity of murine allergic asthma as evidenced histologically, and measurement of allergen-specific IgE levels in serum as well as in BAL fluid. BCA also reversed the elevated levels of inflammatory cytokines, cell infiltration, protein leakage into the airways and expression of hemoxygenase-1 in OVA-induced lungs. Further, we confirmed that BCA mediated inhibitory effects are mediated through PPARγ as assessed by treatment with PPARγ antagonist GW9662., Conclusion: Our results suggest that BCA is efficacious in a preclinical model of asthma and may have the potential for the treatment of asthma in humans., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Bovine respiratory disease (BRD) is the most common disease in beef cattle and leads to considerable economic losses in both beef and dairy cattle. It is important to uncover the molecular mechanisms underlying BRD and to identify biomarkers for early identification of BRD cattle in order to address its impact on production and welfare. In this study, a longitudinal transcriptomic analysis was conducted using blood samples collected from 24 beef cattle at three production stages in the feedlot: 1) arrival (Entry group); 2) when identified as sick (diagnosed as BRD) and separated for treatment (Pulled); 3) prior to marketing (Close-out, representing healthy animals). Expressed genes were significantly different in the same animal among Entry, Pulled and Close-out stages (false discovery rate (FDR) < 0.01 & |Fold Change| > 2). Beef steers at both Entry and Pulled stages presented obvious difference in GO terms (FDR < 0.05) and affected biological functions (FDR < 0.05 & |Z-score| > 2) when compared with animals at Close-out. However, no significant functional difference was observed between Entry and Pulled animals. The interferon signaling pathway showed the most significant difference between animals at Entry/Pulled and Close-out stages (P < .001 & |Z-score| > 2), suggesting the animals initiated antiviral responses at an early stage of infection. Six key genes including IFI6, IFIT3, ISG15, MX1, and OAS2 were identified as biomarkers to predict and recognize sick cattle at Entry. A gene module with 169 co-expressed genes obtained from WGCNA analysis was most positively correlated (R = 0.59, P = 6E-08) with sickness, which was regulated by 11 transcription factors. Our findings provide an initial understanding of the BRD infection process in the field and suggests a subset of novel marker genes for identifying BRD in cattle at an early stage of infection., (Copyright © 2020. Published by Elsevier Inc.)

MicroRNAs (miRNAs) are short single-stranded RNAs that have pivotal roles in disease pathophysiology through transcriptional and translational modulation of important genes. It has been implicated in the development of many diseases, such as stroke, cardiovascular conditions, cancers and inflammatory airway diseases. There is recent evidence that miRNAs play important roles in the pathogenesis of asthma and chronic obstructive pulmonary disease (COPD), and could help to distinguish between T2-low (non-eosinophilic, steroid-insensitive) versus T2-high (eosinophilic, steroid-sensitive) disease endotypes. As these are the two most prevalent chronic respiratory diseases globally, with rising disease burden, miRNA research might lead to the development of new diagnostic and therapeutic targets. Research involving miRNAs in airway disease is challenging because: (i) asthma and COPD are heterogeneous inflammatory airway diseases; there are overlapping but distinct inter- and intra-disease differences in the immunological pathophysiology, (ii) there exists more than 2000 known miRNAs and a single miRNA can regulate multiple targets, (iii) differential effects of miRNAs could be present in different cellular subtypes and tissues, and (iv) dysregulated miRNA expression might be a direct consequence of an indirect effect of airway disease onset or progression. As miRNAs are actively secreted in fluids and remain relatively stable, they have the potential for biomarker development and therapeutic targets. In this review, we summarize the preclinical data on potential miRNA biomarkers that mediate different pathophysiological mechanisms in airway disease. We discuss the framework for biomarker development using miRNA and highlight the need for careful patient characterization and endotyping in the screening and validation cohorts, profiling both airway and blood samples to determine the biological fluids of choice in different disease states or severity, and adopting an untargeted approach. Collaboration between the various stakeholders - pharmaceutical companies, laboratory professionals and clinician-scientists is crucial to reduce the difficulties and cost required to bring miRNA research into the translational stage for airway diseases., (Copyright © 2020. Published by Elsevier Ltd.)

Founder mutations and autosomal recessive (AR) disorders are common in the Arabian Peninsula due to frequent consanguineous marriages. As a result, the pulmonary service at Tawam Hospital (Al Ain, UAE) routinely requests genetic testing for children with persistent (unexplained) respiratory problems. The main purpose of this report was to underscore the usefulness of these tests. Ten children with severe respiratory diseases due to complex genetic findings are described here. Forty-one variants (six novel) were detected, averaging four per patient (range: 1-9). Seven (17%) variants were homozygous and 34 (83%) heterozygous; some variants were known to show monoallelic expression. Using binomial probability distribution, the fetal-risk for having AR disorder(s) as a function of the number of shared variants by a couple ranged from 0.25 (having one shared variant) to 0.9249 (having nine shared variants). In cultures where increased size of homozygous genomic segments is common, children often have multiple variants that could cause complex clinical phenotypes. Identifying pathogenic variants assists in clinical care, family counseling, and disease prevention through genetic screening., (© 2020 Wiley Periodicals LLC.)

Genetic factors influence the development of guttural pouch tympany, recurrent laryngeal neuropathy, severe equine asthma, exercise-induced pulmonary hemorrhage, and possibly also some malformations and infectious diseases of the respiratory tract. The current data suggest that most of these diseases are complex, resulting from the interaction between several genes and environmental factors. To date, no specific genes or causative mutations have been identified that would allow the development of practical genetic tests. In the future, genetic profiling panels, based on multiple genetic markers and environmental risk factors, may allow identification of individuals with an increased genetic risk., Competing Interests: Disclosure The author has no conflict of interest or relevant financial disclosures., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Dysregulation of airway nerves leads to airway hyperreactivity, a hallmark of asthma. Although changes to nerve density and phenotype have been described in asthma, the relevance of these changes to nerve function has not been investigated due to anatomical limitations where afferent and efferent nerves run in the same nerve trunk, making it difficult to assess their independent contributions. We developed a unique and accessible system to activate specific airway nerves to investigate their function in mouse models of airway disease. We describe a method to specifically activate cholinergic neurons using light, resulting in immediate, measurable increases in airway inflation pressure and decreases in heart rate. Expression of light-activated channelrhodopsin 2 in these neurons is governed by Cre expression under the endogenous choline acetyltransferase promoter, and we describe a method to decrease variability in channelrhodopsin expression in future experiments. Optogenetic activation of specific subsets of airway neurons will be useful for studying the functional relevance of other observed changes, such as changes to nerve morphology and protein expression, across many airway diseases, and may be used to study the function of subpopulations of autonomic neurons in lungs and other organs.

Bovine respiratory disease (BRD) is a multifactorial disease complex and the leading infectious disease in post-weaned beef cattle. Clinical manifestations of BRD are recognized in beef calves within a high-risk setting, commonly associated with weaning, shipping, and novel feeding and housing environments. However, the understanding of complex host immune interactions and genomic mechanisms involved in BRD susceptibility remain elusive. Utilizing high-throughput RNA-sequencing, we contrasted the at-arrival blood transcriptomes of 6 beef cattle that ultimately developed BRD against 5 beef cattle that remained healthy within the same herd, differentiating BRD diagnosis from production metadata and treatment records. We identified 135 differentially expressed genes (DEGs) using the differential gene expression tools edgeR and DESeq2. Thirty-six of the DEGs shared between these two analysis platforms were prioritized for investigation of their relevance to infectious disease resistance using WebGestalt, STRING, and Reactome. Biological processes related to inflammatory response, immunological defense, lipoxin metabolism, and macrophage function were identified. Production of specialized pro-resolvin mediators (SPMs) and endogenous metabolism of angiotensinogen were increased in animals that resisted BRD. Protein-protein interaction modeling of gene products with significantly higher expression in cattle that naturally acquire BRD identified molecular processes involving microbial killing. Accordingly, identification of DEGs in whole blood at arrival revealed a clear distinction between calves that went on to develop BRD and those that resisted BRD. These results provide novel insight into host immune factors that are present at the time of arrival that confer protection from BRD., Competing Interests: The authors have declared that no competing interests exist.

Non-steroidal anti-inflammatory drugs (NSAID) exacerbated respiratory disease (N-ERD) is a disease integrated by asthma, nasal polyps, and hypersensitivity to non-steroidal anti-inflammatory drugs (NSAID). Genetic association studies have explored single nucleotide polymorphisms (SNPs) in genes involved in theoretical pathophysiological mechanisms, but most of these lack replication of findings in second populations. Our objective was to evaluate the association of SNPs in candidate genomic regions described in Asian and European subjects with N-ERD in Mexican-mestizo patients. We designed a replicative study in two stages. We included 381 SNPs selected by fine mapping of associated genes in a microarray, which were tested in three groups: N-ERD (N), asthma (A), and control group (CG); by means of GoldenGate array, positive results by genetic models were validated in the second stage in another population through qPCR with the same methodology. In the allelic model, we identified 11 SNPs in N vs. CG comparison, and five in N vs. A and A vs. CG, respectively. By genetics models, all SNPs in PPARG , rs13239058 in TBXAS1 , and rs1554286 and rs1800872 in IL10 were associated in both models. In the second stage, only rs1800872CC showed an association in the dominant model comparing N vs. GC, p = 0.004, OR = 0.44. In conclusion, rs1800872 in IL10 was the only associated with N-ERD in Mexican-mestizo patients.

Purpose of Review: Epithelial barrier defects are being appreciated in various inflammatory disorders; however, causal underlying mechanisms are lacking. In this review, we describe the disruption of the airway epithelium with regard to upper and lower airway diseases, the role of epigenetic alterations underlying this process, and potential novel ways of interfering with dysfunctional epithelial barriers as a novel therapeutic approach., Recent Findings: A defective epithelial barrier, impaired innate defence mechanisms or hampered epithelial cell renewal are found in upper and lower airway diseases. Barrier dysfunction might facilitate the entrance of foreign substances, initiating and facilitating the onset of disease. Latest data provided novel insights for possible involvement of epigenetic alterations induced by inflammation or other unknown mechanisms as a potential mechanism responsible for epithelial defects. Additionally, these mechanisms might precede disease development, and represent a novel therapeutic approach for restoring epithelial defects., Summary: A better understanding of the role of epigenetics in driving and maintaining epithelial defects in various inflammatory diseases, using state-of-the-art biology tools will be crucial in designing novel therapies to protect or reconstitute a defective airway epithelial barrier.

Precision medicine represents a potentially powerful means to alleviate the growing burden of chronic respiratory diseases. To realise its potential, however, we need a systems level understanding of how biological events (signalling pathways, cell-cell interactions, tissue mechanics) integrate across multiple spatial and temporal scales to give rise to pathology. This can be achieved most practically in silico: a paradigm that offers tight control over model parameters and rapid means of testing and generating mechanistic hypotheses. Patient-specific computational models that can enable identification of pathological mechanisms unique to patients' (omics, physiological, and anatomical) profiles and, therefore, personalised drug targets represent a major milestone in precision medicine. Current patient-based models in literature, especially medical devices, cardiac modelling, and respiratory medicine, rely mostly on (partial/ordinary) differential equations and have reached relatively advanced level of maturity. In respiratory medicine, patient-specific simulations mainly include subject scan-based lung mechanics models that can predict pulmonary function, but they treat the (sub)cellular processes as "black-boxes". A recent advance in simulating human airways at a cellular level to make clinical predictions raises the possibility of linking omics and cell level data/models with lung mechanics to understand respiratory pathology at a systems level. This is significant as this approach can be extended to understanding pathologies in other organs as well. Here, I will discuss ways in which computational models have already made contributions to personalised healthcare and how the paradigm can expedite clinical uptake of precision medicine strategies. I will mainly focus on an agent-based, asthmatic virtual patient that predicted the impact of multiple drug pharmacodynamics at the patient level, its potential to develop efficacious precision medicine strategies in respiratory medicine, and the regulatory and ethical challenges accompanying the mainstream application of such models., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

The serine-threonine kinase homeodomain-interacting protein kinase 2 (HIPK2) modulates important cellular functions during development, acting as a signal integrator of a wide variety of stress signals, and as a regulator of transcription factors and cofactors. We have previously demonstrated that HIPK2 binds and phosphorylates High-Mobility Group A1 (HMGA1), an architectural chromatinic protein ubiquitously expressed in embryonic tissues, decreasing its binding affinity to DNA. To better define the functional role of HIPK2 and HMGA1 interaction in vivo, we generated mice in which both genes are disrupted. About 50% of these Hmga1/Hipk2 double knock-out (DKO) mice die within 12 h of life (P1) for respiratory failure. The DKO mice present an altered lung morphology, likely owing to a drastic reduction in the expression of surfactant proteins, that are required for lung development. Consistently, we report that both HMGA1 and HIPK2 proteins positively regulate the transcriptional activity of the genes encoding the surfactant proteins. Moreover, these mice display an altered expression of thyroid differentiation markers, reasonably because of a drastic reduction in the expression of the thyroid-specific transcription factors PAX8 and FOXE1, which we demonstrate here to be positively regulated by HMGA1 and HIPK2. Therefore, these data indicate a critical role of HIPK2/HMGA1 cooperation in lung and thyroid development and function, suggesting the potential involvement of their impairment in the pathogenesis of human lung and thyroid diseases.

Purpose: Particulate matter (PM) has been implicated as a risk factor for airway injury. However, the molecular mechanisms remain largely unclear. The goal of this study was to determine whether sirtuin1 (SIRT1), an anti-inflammatory and antiaging protein, protects against PM-induced airway inflammation., Methods: The effect of SIRT1 on PM-induced airway inflammation was assessed by using in vivo models of airway inflammation induced by PM and in vitro culture of human bronchial epithelial (HBE) cells exposed to PM, resveratrol (SIRT1 activator), or both., Results: PM-stimulated HBE cells showed a significant decrease in SIRT1 but a notable increase in inflammatory cytokines. SIRT1 gene silencing further enhanced PM-induced expression of inflammatory cytokines. In contrast, resveratrol, a SIRT1 activator, reduced the expression of these cytokines compared with the control cells. In vivo, SIRT1 expression was significantly decreased in lung tissues of PM-exposed mice. Interestingly, resveratrol treatment reversed the enhanced total cells, neutrophils and inflammatory cytokines in PM-induced mice. Moreover, SIRT1 mediated PM-induced inflammatory cytokines expression at least partly through MAPK pathways., Conclusion: These findings suggest that SIRT1 is involved in the pathogenesis of PM-induced airway inflammation and activation of SIRT1 could prevent airway disorders or disease exacerbations induced by airborne particulate pollution., Competing Interests: The authors declare that they have no conflicts of interest regarding this manuscript.

Respiratory diseases, such as influenza infection, acute tracheal bronchitis, pneumonia, tuberculosis, chronic obstructive pulmonary disease, asthma, lung cancer and nasopharyngeal carcinoma, continue to significantly impact human health. Diseases of the lung and respiratory tract are influenced by environmental conditions and socio-economic factors; however, many of these serious respiratory disorders are also rooted in genetic or epigenetic causes. Clustered regularly interspaced palindromic repeats (CRISPR) and CRISPR-associated (Cas) proteins, isolated from the immune system of prokaryotes, provide a tool to manipulate gene sequences and gene expression with significant implications for respiratory research. CRISPR/Cas systems allow preclinical modelling of causal factors involved in many respiratory diseases, providing new insights into their underlying mechanisms. CRISPR can also be used to screen for genes involved in respiratory processes, development and pathology, identifying novel disease drivers or drug targets. Finally, CRISPR/Cas systems can potentially correct genetic mutations and edit epigenetic marks that contribute to respiratory disorders, providing a form of personalized medicine that could be used in conjunction with other technologies such as stem cell reprogramming and transplantation. CRISPR gene editing is a young field of research, and concerns regarding its specificity, as well as the need for efficient and safe delivery methods, need to be addressed further. However, CRISPR/Cas systems represent a significant step forward for research and therapy in respiratory health, and it is likely we will see the breakthroughs generated from this technology continue., (© 2019 Asian Pacific Society of Respirology.)

The contribution of epithelial-mesenchymal transition (EMT) to human lung fibrogenesis is controversial. Here we provide evidence that ZEB1-mediated EMT in human alveolar epithelial type II (ATII) cells contributes to the development of lung fibrosis by paracrine signalling to underlying fibroblasts. Activation of EGFR-RAS-ERK signalling in ATII cells induced EMT via ZEB1. ATII cells had extremely low extracellular matrix gene expression even after induction of EMT, however conditioned media from ATII cells undergoing RAS-induced EMT augmented TGFβ-induced profibrogenic responses in lung fibroblasts. This epithelial-mesenchymal crosstalk was controlled by ZEB1 via the expression of tissue plasminogen activator (tPA). In human fibrotic lung tissue, nuclear ZEB1 expression was detected in alveolar epithelium adjacent to sites of extracellular matrix (ECM) deposition, suggesting that ZEB1-mediated paracrine signalling has the potential to contribute to early fibrotic changes in the lung interstitium. Targeting this novel ZEB1 regulatory axis may be a viable strategy for the treatment of pulmonary fibrosis.

Mycoplasma gallisepticum ( MG ) mainly infects chickens to initiate chronic respiratory disease (CRD). microRNAs (miRNAs) play vital roles according to previously reported studies. Our previous study showed that gga-miR-16-5p, in MG -infected lungs of chicken embryo, was upregulated by Illumina sequencing. The study aimed to reveal what role gga-miR-16-5p plays in CRD progression. gga-miR-16-5p was upregulated in MG -infected fibroblast cells (DF-1). Phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1) was demonstrated as the target gene of gga-miR-16-5p. Furthermore, PIK3R1 expression was lower in MG -infected groups than it in noninfected controls measured by qPCR. Additionally, overexpressed gga-miR-16-5p could downregulate PIK3R1 and phosphorylated serine/threonine kinase (p-Akt) to express protein, whereas there is an opposite effect on inhibition. Overexpressed gga-miR-16-5p resulted in decreased activity of tumor necrosis factor alpha (TNF-α) and the nuclear factor-kappaB (NF-κB) by qPCR. Furthermore, overexpressed gga-miR-16-5p restricted cell multiplication, cycle progression, and increased apoptosis of MG -infected DF-1 cells, whereas inhibited gga-miR-16-5p led to the opposite effect. Collectively, upregulated gga-miR-16-5p could decrease multiplication, cycle progression, and increase apoptosis of MG -infected DF-1 cells, at least partly through directly targeting PIK3R1 and inhibiting PI3K/Akt/NF-κB pathway to exert an anti-inflammatory effect. Our results will provide more experimental evidence to bring pathogenesis of MG infection to light.

Respiratory symptoms are important indicators of respiratory diseases. Both genetic and environmental factors contribute to respiratory symptoms development but less is known about gene-environment interactions. We aimed to assess interactions between single nucleotide polymorphisms (SNPs) and occupational exposures on respiratory symptoms cough, dyspnea and phlegm. As identification cohort LifeLines I (n = 7976 subjects) was used. Job-specific exposure was estimated using the ALOHA + job exposure matrix. SNP-by-occupational exposure interactions on respiratory symptoms were tested using logistic regression adjusted for gender, age, and current smoking. SNP-by-exposure interactions with a p-value <10 -4 were tested for replication in two independent cohorts: LifeLines II (n = 5260) and the Vlagtwedde-Vlaardingen cohort (n = 1529). The interaction estimates of the replication cohorts were meta-analyzed using PLINK. Replication was achieved when the meta-analysis p-value was <0.05 and the interaction effect had the same direction as in the identification cohort. Additionally, we assessed whether replicated SNPs associated with gene expression by analyzing if they were cis-acting expression quantitative trait loci (eQTL) in lung tissue. In the replication meta-analysis, sixteen out of 477 identified SNP-by-occupational exposure interactions had a p-value <0.05 and 9 of these interactions had the same direction as in the identification cohort. Several identified loci were plausible candidates for respiratory symptoms, such as TMPRSS9, SERPINH1, TOX3, and ARHGAP18. Three replicated SNPs were cis-eQTLs for FCER1A, CHN1, and TIMM13 in lung tissue. Taken together, this genome-wide SNP-by-occupational exposure interaction study in relation to cough, dyspnea, and phlegm identified several suggestive susceptibility genes. Further research should determine if these genes are true susceptibility loci for respiratory symptoms in relation to occupational exposures., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Bovine respiratory disease (BRD) is a complex disease that is associated with infection by bacterial and viral pathogens when cattle fail to adequately respond to stress. The objective of this study was to use gene set enrichment analysis of SNP data (GSEA-SNP) and a network analysis (ingenuity pathway analysis) to identify gene sets, genes within gene sets (leading-edge genes) and upstream regulators associated with BRD in pre-weaned dairy calves and beef feedlot cattle. BRD cases and controls were diagnosed using the McGuirk health scoring system. Holstein calves were sampled from commercial calf-raising facilities in California (1003 cases and 1011 controls) and New Mexico (376 cases and 372 controls). Commercial feedlot cattle were sampled from Colorado (500 cases and 499 controls) and Washington (504 cases and 497 controls). There were 102 and 237 unique leading-edge genes identified in the dairy calf and beef cattle populations respectively. Six leading-edge genes (ADIPOQ, HTR2A, MIF, PDE6G, PRDX3 and SNCA) were associated with BRD in both dairy and beef cattle. Network analysis identified glucose as the most influential upstream regulator in dairy cattle, whereas in beef cattle, TNF was the most influential upstream regulator. The genes, gene sets and upstream regulators associated with BRD have common functions associated with immunity, inflammation and pulmonary disease and provide insights into the mechanisms that are critical to BRD susceptibility in cattle., (© 2018 Stichting International Foundation for Animal Genetics.)

Respiratory diseases such as asthma, chronic obstructive pulmonary disease and lung cancer represent a critical area for medical research as millions of people are affected globally. The development of new strategies for treatment and/or prevention, and the identification of biomarkers for patient stratification and early detection of disease inception are essential to reducing the impact of lung diseases. The successful translation of research into clinical practice requires a detailed understanding of the underlying biology. In this regard, the advent of next-generation sequencing and mass spectrometry has led to the generation of an unprecedented amount of data spanning multiple layers of biological regulation (genome, epigenome, transcriptome, proteome, metabolome and microbiome). Dealing with this wealth of data requires sophisticated bioinformatics and statistical tools. Here, we review the basic concepts in bioinformatics and genomic data analysis and illustrate the application of these tools to further our understanding of lung diseases. We also highlight the potential for data integration of multi-omic profiles and computational drug repurposing to define disease subphenotypes and match them to targeted therapies, paving the way for personalized medicine., (© 2018 Asian Pacific Society of Respirology.)

A single-nucleotide polymorphism (rs35705950) in the mucin 5B ( MUC5B ) gene promoter is associated with pulmonary fibrosis and interstitial features on chest CT but may also have beneficial effects. In non-Hispanic whites in the COPDGene cohort with interstitial features (n=454), the MUC5B promoter polymorphism was associated with a 61% lower odds of a prospectively reported acute respiratory disease event (P=0.001), a longer time-to-first event (HR=0.57; P=0.006) and 40% fewer events (P=0.016). The MUC5B promoter polymorphism may have a beneficial effect on the risk of acute respiratory disease events in smokers with interstitial CT features., Competing Interests: Competing interests: SYA, RH, RKP and RSJE report no other relevant disclosures. GMH reports consulting for Medna LLC, and Gerson Lehrman Group, and has served on a scientific advisory boards for Genentech and Boehringer-Ingelheim. GRW reports other support from Genentech, GlaxoSmithKline, PulmonX, and Janssen., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

The proteome is the study of the protein content of a definable component of an organism in biology. However, the tissue-specific expression of proteins and the varied post-translational modifications, splice variants and protein-protein complexes that may form, make the study of protein a challenging yet vital tool in answering many of the unanswered questions in medicine and biology to date. Indeed, the spatial, temporal and functional composition of proteins in the human body has proven difficult to elucidate for many years. Given the effect of microRNA and epigenetic regulation on silencing and enhancing gene transcription, the study of protein arguably provides more accurate information on homeostasis and perturbation in health and disease. There have been significant advances in the field of proteomics in recent years, with new technologies and platforms available to the research community. In this review, we briefly discuss some of these new technologies and developments in the context of respiratory disease. We also discuss the types of data science approaches to analyses and interpretation of the large volumes of data generated in proteomic studies. We discuss the application of these technologies with regard to respiratory disease and highlight the potential for proteomics in generating major advances in the understanding of respiratory pathophysiology into the future., (© 2018 Asian Pacific Society of Respirology.)

Poisoning from pesticides is a global public health problem and accounts for nearly 300,000 deaths worldwide every year. Exposure to pesticides is inevitable; there are different modes through which humans get exposed to pesticides. The mode of exposure is an important factor as it also signifies the concentration of pesticides exposure. Pesticides are used extensively in agricultural and domestic settings. These chemicals are believed to cause many disorders in humans and wildlife. Research from past few decades has tried to answer the associated mechanism of action of pesticides in conjunction with their harmful effects. This perspective considers the past and present research in the field of pesticides and associated disorders. We have reviewed the most common diseases including cancer which are associated with pesticides. Pesticides have shown to be involved in the pathogenesis of Parkinson's and Alzheimer's diseases as well as various disorders of the respiratory and reproductive tracts. Oxidative stress caused by pesticides is an important mechanism through which many of the pesticides exert their harmful effects. Oxidative stress is known to cause DNA damage which in turn may cause malignancies and other disorders. Many pesticides have shown to modulate the gene expression at the level of non-coding RNAs, histone deacetylases, DNA methylation patterns suggesting their role in epigenetics., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Porcine respiratory disease complex (PRDC), a common piglet disease, causes substantive economic losses in pig farming. To investigate the viral diversity associated with PRDC, the viral communities in serum and nasal swabs from 26 PRDC-affected piglets were investigated using metagenomics. By deep sequencing and de novo assembly, 17 viruses were identified in two pooled libraries (16 viruses from serum, nine from nasal swabs). Porcine circovirus (PCV)-2, porcine reproductive and respiratory syndrome virus (PRRSV) and pseudorabies virus, all commonly associated with PRDC, were identified in the two pooled samples by metagenomics, but most viruses comprised small linear and circular DNAs (e.g. parvoviruses, bocaviruses and circoviruses). PCR was used to compare the detection rates of each virus in the serum samples from 36 PRDC-affected piglets versus 38 location-matched clinically healthy controls. The average virus category per sample was 6.81 for the PRDC-affected piglets and 4.09 for the controls. Single or co-infections with PCV-2 or PRRSV had very high detection rates in the PRDC-affected piglets. Interestingly, porcine parvovirus (PPV)-2, PPV-3, PPV-6 and torque teno sus virus 1a were significantly associated with PRDC. These results illustrate the complexity of viral communities in the PRDC-affected piglets and highlight the candidate viruses associated with it.

Exposure to particulate matter < 2.5 μm (PM 2.5 ) is associated with a variety of airway diseases. Although studies have demonstrated that high doses of PM 2.5 cause cytotoxicity and changes to gene expression in bronchial epithelial cells, the effect of lower doses and repeated exposure to PM 2.5 are less well studied. Here, we treated BEAS-2B cells with varying doses of PM 2.5 for 1-7 days and examined the expression of a variety of genes implicated in airway disorders. At high doses, PM 2.5 increased the expression of IL6, TNF, TSLP, CSF2, PTGS2, IL4R, and SPINK5. Other genes such as ADAM33, ORMDL3, DPP10 and CYP1A1, however, were increased by PM 2.5 at much lower doses (≤1 μg/cm 2 ). Repeated exposure to PM 2.5 at 1 or 5 μg/cm 2 every day for 7 days increased the sensitivity and magnitude of change for all of the aforementioned genes. Genes such as IL13 and TGFB1, increased only when cells were repeatedly exposed to PM 2.5 . Treatment with an antioxidant, or inhibitors to aryl hydrocarbon receptor or NF-κB attenuated the effect of PM 2.5 . These data demonstrate that PM 2.5 exerts pleiotropic actions that differ by dose and duration that affect a variety of genes important to the development of airway disease., (Copyright © 2018 Elsevier Ltd. All rights reserved.)