Journal of respiratory biology and translational medicine最新文献

Asthma is a common respiratory disorder characterized by chronic inflammation of the lower airways, contributing to significant morbidity, mortality, and a substantial global economic burden. It is now understood as a heterogeneous condition, with ongoing research shedding light on its complex immunological underpinnings. Ion channels, which are specialized transmembrane proteins that facilitate ion movement based on electrochemical gradients, play a crucial role in the pathophysiology of asthma. Ion channels regulate essential processes like maintaining epithelial hydroelectrolyte balance and also play a role in modulating immune responses involved in asthma. We discuss the connection between ion channel activity and immune regulation in asthma, focusing on ion channel regulation of immune cell behavior, airway hyperresponsiveness, and inflammation in asthma. Understanding ion channels in asthma could lead to the development of targeted therapies modulating their activity, thereby enhancing disease management and patient outcomes.

Asthma affects millions worldwide and involves complex genetic, immunological, and environmental factors. The nasal microbiome is increasingly recognized for its role in asthma development, but inconsistent results and small sample sizes have limited a clear understanding. We aimed to clarify the nasal microbiome's role in asthma using large datasets and meta-transcriptomic analysis. RNA-seq data was analyzed from two large public studies: GALA II (694 children of Puerto Rican heritage; 441 asthmatics, 253 controls) and CAAPA (562 individuals of African ancestry; 265 asthmatics, 297 controls). After quality control and host read removal, microbial reads were annotated using Kraken2. α and β diversity analyses compared microbial diversity between asthmatic and control groups. Differential abundance analysis was conducted separately, controlling for age and sex, with results combined via meta-analysis. We found that asthmatic patients exhibited significantly higher α diversity indices (Shannon, Berger-Parker, Inverse Simpson, Fisher's) in nasal microbiota compared to controls in GALA II, with similar trends in CAAPA. β diversity analysis showed significant differences in microbial composition in GALA II data. Differential abundance analysis identified 20 species in GALA II and 9 species in CAAPA significantly associated with asthma. Meta-analysis revealed 11 species significantly associated with asthma, including Mycobacterium_tuberculosis. Our study demonstrates increased nasal microbiome α diversity in asthmatic patients and identifies specific microbial species associated with asthma risk. These findings enhance understanding of asthma pathogenesis from the nasal microbiome perspective and may inform future research and therapeutic strategies.

It is well established that Nrf2 plays a crucial role in anti-oxidant and anti-inflammatory functions. However, its antiviral capabilities remain less explored. Despite this, several Nrf2 activators have demonstrated anti-SARS-CoV-2 properties, though the mechanisms behind these effects are not fully understood. In this study, using two mouse models of SARS-CoV-2 infection, we observed that the absence of Nrf2 significantly increased viral load and altered inflammatory responses. Additionally, we evaluated five Nrf2 modulators. Notably, epigallocatechin gallate (EGCG), sulforaphane (SFN), and dimethyl fumarate (DMF) exhibited significant antiviral effects, with SFN being the most effective. SFN did not impact viral entry but appeared to inhibit the main protease (M^Pro) of SARS-CoV-2, encoded by the Nsp5 gene, as indicated by two protease inhibition assays. Moreover, using two Nrf2 knockout cell lines, we confirmed that SFN's antiviral activity occurs independently of Nrf2 activation in vitro. Paradoxically, in vivo tests using the MA30 model showed that SFN's antiviral function was completely lost in Nrf2 knockout mice. Thus, although SFN and potentially other Nrf2 modulators can inhibit SARS-CoV-2 independently of Nrf2 activation in cell models, their Nrf2-dependent activities might be crucial for antiviral defense under physiological conditions.

Human alveolar type I (AT1) cells are specialized epithelial cells that line the alveoli in the lungs where gas exchange occurs. The primary function of AT1 cells is not only to facilitate efficient gas exchange between the air and the blood in the lungs, but also to contribute to the structural integrity of the alveoli to maintain lung function and homeostasis. Aging has notable effects on the structure, function, and regenerative capacity of human AT1 cells. However, our understanding of the molecular mechanisms driving these age-related changes in AT1 cells remains limited. Leveraging a recent single-cell transcriptomics dataset we generated on healthy human lungs, we identified a series of significant molecular alterations in AT1 cells from aged lungs. Notably, the aged AT1 cells exhibited increased cellular senescence and chemokine gene expression, alongside diminished epithelial features such as decreases in cell junctions, endocytosis, and pulmonary matrisome gene expression. Gene set analyses also indicated that aged AT1 cells were resistant to apoptosis, a crucial mechanism for turnover and renewal of AT1 cells, thereby ensuring alveolar integrity and function. Further research on these alterations is imperative to fully elucidate the impact on AT1 cells and is indispensable for developing effective therapies to preserve lung function and promote healthy aging.

The conducting airways of the respiratory system play a crucial role in filtering, humidifying, and directing air into the lungs. Among the specialized cell types within these airways, airway serous cells are notable for their secretion of watery, protein-rich fluids and enzymes, which contribute to maintaining airway surface liquid homeostasis and defending against pathogens. However, the distribution and abundance of serous cells across different species in the conducting airways remain poorly understood. In this study, we addressed this gap by investigating the spatial distribution of the airway serous cell-specific marker BPI fold containing family A member 1 (BPIFA1) in humans, pigs, and mice. Our findings demonstrate significant variations in the distribution and abundance of serous cells among these species, potentially reflecting their different respiratory anatomy and evolutionary adaptations to diverse environmental challenges and respiratory demands. In humans and pigs, airway serous cells are predominantly found in the submucosal glands of the trachea and segmental bronchi, frequently overlapping with lysozyme-positive secretory cells. In contrast, rodents like mice exhibit a distinct pattern where serous cells are scarce in submucosal glands. Instead, rodent serous cells are primarily located at the epithelial surface from the trachea to the main bronchi, where many co-express the Club cell-specific protein SCGB1A1. The abundance of serous cells diminishes progressively in the intrapulmonary airways. Given that rodent models are widely utilized in respiratory research, understanding anatomical and cellular differences in airway serous cells is critical for interpreting experimental outcomes and translating findings to human respiratory diseases and therapeutic strategies. This comparative analysis enhances our understanding of airway biology across species and informs the selection and interpretation of animal models in respiratory studies.

The ubiquitin system has been shown to play an important role in regulation of immune responses during viral infection. In a recent article published in Science Signaling, Wu and colleagues revealed that transcriptional factor Miz1 plays a pro-viral role in influenza A virus (IAV) infection by suppressing type I interferons (IFNs) production through recruiting HDAC1 to ifnb1 promoter. They show that a series of E3 ligases combinatorially regulates Miz1 ubiquitination and degradation and modulates IFNs production and viral replication.

The molecular mechanisms that regulate progressive pulmonary fibrosis remain poorly understood. Type 2 alveolar epithelial cells (AEC2s) function as adult stem cells in the lung. We previously showed that there is a loss of AEC2s and a failure of AEC2 renewal in the lungs of idiopathic pulmonary fibrosis (IPF) patients. We also reported that beta-arrestins are the key regulators of fibroblast invasion, and beta-arrestin 1 and 2 deficient mice exhibit decreased mortality, decreased matrix deposition, and increased lung function in bleomycin-induced lung fibrosis. However, the role of beta-arrestins in AEC2 regeneration is unclear. In this study, we investigated the role and mechanism of Arrestin beta 1 (ARRB1) in AEC2 renewal and in lung fibrosis. We used conventional deletion as well as cell type-specific deletion of ARRB1 in mice and found that Arrb1 deficiency in fibroblasts protects mice from lung fibrosis, and the knockout mice exhibit enhanced AEC2 regeneration in vivo, suggesting a role of fibroblast-derived ARRB1 in AEC2 renewal. We further found that Arrb1-deficient fibroblasts promotes AEC2 renewal in 3D organoid assays. Mechanistically, we found that CCL7 is among the top downregulated cytokines in Arrb1 deficient fibroblasts and CCL7 inhibits AEC2 regeneration in 3D organoid experiments. Therefore, fibroblast ARRB1 mediates AEC2 renewal, possibly by releasing chemokine CCL7, leading to fibrosis in the lung.

Pulmonary arterial hypertension (PAH) is a devastating disease characterized by high blood pressure in the pulmonary arteries, which can potentially lead to heart failure over time. Previously, our lab found that endothelia-specific knockout of Egln1, encoding prolyl 4-hydroxylase-2 (PHD2), induced spontaneous pulmonary hypertension (PH). Recently, we elucidated that Tmem100 is a lung-specific endothelial gene using Tmem100-CreERT2 mice. We hypothesize that lung endothelial-specific deletion of Egln1 could lead to the development of PH without affecting Egln1 gene expression in other organs. Tmem100-CreERT2 mice were crossed with Egln1 ^flox/flox mice to generate Egln1 ^f/f ;Tmem100-CreERT2 (LiCKO) mice. Western blot and immunofluorescent staining were performed to verify the knockout efficacy of Egln1 in multiple organs of LiCKO mice. PH phenotypes, including hemodynamics, right heart size and function, pulmonary vascular remodeling, were evaluated by right heart catheterization and echocardiography measurements. Tamoxifen treatment induced Egln1 deletion in the lung endothelial cells (ECs) but not in other organs of adult LiCKO mice. LiCKO mice exhibited an increase in right ventricular systolic pressure (RVSP, ~35 mmHg) and right heart hypertrophy. Echocardiography measurements showed right heart hypertrophy, as well as cardiac and pulmonary arterial dysfunction. Pulmonary vascular remodeling, including increased pulmonary wall thickness and muscularization of distal pulmonary arterials, was enhanced in LiCKO mice compared to wild-type mice. Tmem100 promoter-mediated lung endothelial knockout of Egln1 in mice leads to development of spontaneous PH. LiCKO mice could serve as a novel mouse model for PH to study lung and other organ crosstalk.

Asthma is a prevalent respiratory condition with multifaceted pathomechanisms, presenting challenges for therapeutic development. The SLC (Solute Carrier) gene family, encompassing diverse membrane transport proteins, plays pivotal roles in various human diseases by facilitating solute movement across biological membranes. These solutes include ions, sugars, amino acids, neurotransmitters, and drugs. Mutations in these ion channels have been associated with numerous disorders, underscoring the significance of SLC gene families in physiological processes. Among these, the SLC26A4 gene encodes pendrin, an anion exchange protein involved in transmembrane transport of chloride, iodide, and bicarbonate. Mutations in SLC26A4 are associated with Pendred syndrome. Elevated SLC26A4 expression has been linked to airway inflammation, hyperreactivity, and mucus production in asthma. Here, we review novel insights from SLC gene family members into the mechanisms of substrate transport and disease associations, with specific emphasis on SLC26A4. We explore triggers inducing SLC26A4 expression and its contributions to the pathogenesis of pulmonary diseases, particularly asthma. We summarize the inhibitors of SLC26A4 that have shown promise in the treatment of different phenotypes of diseases. While SLC26A4 inhibitors present potential treatments for asthma, further research is imperative to delineate their precise role in asthma pathogenesis and develop efficacious therapeutic strategies targeting this protein.

Tissue lymphatic vessels network plays critical roles in immune surveillance and tissue homeostasis in response to pathogen invasion, but how lymphatic system per se is remolded during infection is less understood. Here, we observed that influenza infection induces a significant increase of lymphatic vessel numbers in the lung, accompanied with extensive proliferation of lymphatic endothelial cells (LECs). Single-cell RNA sequencing illustrated the heterogeneity of LECs, identifying a novel PD-L1⁺ subpopulation that is present during viral infection but not at steady state. Specific deletion of Pd-l1 in LECs elevated the expansion of lymphatic vessel numbers during viral infection. Together these findings elucidate a dramatic expansion of lung lymphatic network in response to viral infection, and reveal a PD-L1⁺ LEC subpopulation that potentially modulates lymphatic vessel remolding.