Increased airway smooth muscle (ASM) mass is believed to underlie the relatively fixed airway hyperresponsiveness (AHR) in asthma. Developments of therapeutic approaches to reverse airway remodeling are impeded by our lack of insight on the mechanisms behind the increase in mass of contractile ASM cells. Increased expression of laminin, an extracellular matrix protein, is associated with asthma. Our studies investigate the role of laminin‐induced ASM survival signals in the development of increased ASM and AHR. Antagonizing laminin integrin binding using the laminin‐selective competing peptide, YIGSR, and mimicking laminin with exogenous α2‐chain laminin, we show that laminin is both necessary and sufficient to induce ASM cell survival, concomitant with the induction of ASM contractile phenotype. Using siRNA, we show that the laminin‐binding integrin α7β1 mediates this process. Moreover, in laminin‐211‐deficient mice, allergen‐induced AHR was not observed. Notably, ASM cells from asthmatic airways express a higher abundance of intracellular cell survival proteins, consistent with a role for reduced rates of cell apoptosis in development of ASM hyperplasia. Targeting the laminin‐integrin α7β1 signaling pathway may offer new avenues for the development of therapies to reduce the increase in mass of contractile phenotype ASM cells that underlie AHR in asthma.—Tran, T., Teoh, C. M., Tam, J. K. C., Qiao, Y., Chin, C. Y., Chong, O. K., Stewart, A. G., Harris, T., Wong, W. S. F., Guan, S. P., Leung, B. P., Gerthoffer, W. T., Unruh, H., and Halayko, A J. Laminin drives survival signals to promote a contractile smooth muscle phenotype and airway hyperreactivity. FASEB J. 27, 3991–4003 (2013). www.fasebj.org

Recent advances in next-generation sequencing and bioinformatics have driven growing interest in the distinct roles of intratumoral microbiota, particularly intracellular bacteria, during tumor evolution. These bacteria increase the likelihood of metastasis, play important roles in cancer progression, and impact therapy efficiency. The present review explores the sources, mechanisms of invasion into cancer cells, and potential survival strategies of intracellular bacteria in neoplasms, highlighting their critical role in cancer development. We also examine the heterogeneity and intricate interplay of intratumoral microbial communities with immune and cancer cells, emphasizing their potential roles in modulating host genetics, epigenetics, and immunity. Finally, we discuss novel approaches to targeting intracellular bacteria, particularly engineered drug delivery systems, and synthetic biology, which aim to enhance bacterial clearance, reprogram the tumor immune microenvironment, and enhance the efficacy of chemotherapy and immunotherapy. As a result, this review provides new insights to guide future investigations and support the development of microbiota-based interventions in oncology.

Idiopathic Pulmonary Fibrosis (IPF) is a chronic fibrotic interstitial lung disease (ILD) of unknown etiology, characterized by increasing incidence and intricate pathogenesis. Current FDA-approved drugs suffer from significant side effects and limited efficacy, highlighting the urgent need for innovative therapeutic agents for IPF. Natural products (NPs), with their multi-target and multifaceted properties, present promising candidates for new drug development. This review delineates the anti-fibrotic pathways and targets of various natural products based on the established pathological mechanisms of IPF. It encompasses over 20 compounds, including flavonoids, saponins, polyphenols, terpenoids, natural polysaccharides, cyclic peptides, deep-sea fungal alkaloids, and algal proteins, sourced from both terrestrial and marine environments. The review explores their potential roles in mitigating pulmonary fibrosis, such as inhibiting inflammatory responses, protecting against lipid peroxidation damage, suppressing mesenchymal cell activation and proliferation, inhibiting fibroblast migration, influencing the synthesis and secretion of pro-fibrotic factors, and regulating extracellular matrix (ECM) synthesis and degradation. Additionally, it covers various in vivo and in vitro disease models, methodologies for analyzing marker expression and signaling pathways, and identifies potential new therapeutic targets informed by the latest research on IPF pathogenesis, as well as challenges in bioavailability and clinical translation. This review aims to provide essential theoretical and technical insights for the advancement of novel anti-pulmonary fibrosis drugs.

Myofibroblasts accumulation contributes to airway remodeling, with the mechanisms being poorly understood. It is steroid-insensitive and has not been therapeutically targeted in asthma. In this study, we explored the potential of yes-associated protein (YAP) as a therapeutic target for myofibroblasts formation in asthma, by revealing the novel role and mechanisms by which YAP activation in type II alveolar epithelial (ATII) cells promotes the fibroblast-to-myofibroblast transition in vitro and in vivo. By performing immunofluorescence staining, we showed that myofibroblasts were increased in the bronchial walls and alveolar parenchyma in clinical asthmatic and house dust mite (HDM)-induced mouse lung samples. This was accompanied by YAP overexpression and nuclear translocation in ATII cells, and connective tissue growth factor (CTGF) upregulation. In vitro, HDM or combination of rhIL-1β with rhTNF-α upregulated and activated YAP in human primary ATII cells and A549 cells, but not in the bronchial epithelial cells, BEAS-2B. This effect was mediated by F-actin polymerization and could be suppressed by pretreatment with latrunculin A but not budesonide. Inhibition of YAP/transcriptional coactivator with PDZ-binding motif (TAZ) in A549 cells by pretreatment with YAP/TAZ siRNA or verteporfin, but not budesonide, impaired the fibroblast-to-myofibroblast transition in vitro. In vivo, verteporfin partly or completely prevented HDM-induced bronchial or alveolar myofibroblast accumulation, and significantly suppressed CTGF expression and collagen deposition in mouse lungs, without profoundly affecting airway inflammation. Our results provide novel mechanistic insights into airway remodeling, and holds promise for the development of novel therapeutic strategies.