Chronic persistent airway inflammation has been associated with the comorbidity of asthma and bipolar disorder (BD). However, the direct relevance between airway inflammation and BD-like psychiatric comorbidity is almost unknown. Integrin β4 (ITGB4) is downregulated on the airway epithelial of asthma patients, which might play a critical role in the parthenogenesis of airway inflammation. So this study aimed to examine the role of ITGB4 deficiency in mediating airway inflammation and further leading to the BD-like behaviors. ITGB4^−/− mice were generated by mating ITGB4^fl/fl mice with CCSP–rtTA^tg/−/TetO-Cretg/tg mice. Mania-like behavior tests were performed, including hyperlocomotion, d-amphetamine-induced hyperactivity, open-field test, and elevated plus-maze test. Depressive-like behavior tests were carried out, including sucrose preference, forced swimming, and learned helplessness. Inflammatory cells (Th17, Th1, Th2) in the lung were examined by flow cytometry. Futhermore, inflammatory cytokines (IL-4, IL-13) in bronchoalveolar lavage fluid and sera were detected by ELISA. Protein expression of the IL-4Rα on choroid plexus, microglial marker (IBA1), and synapse-associated proteins (synaptophysin, SYP) in the hippocampus and prefrontal cortex were examined by western blotting. Additionally, proinflammatory cytokines (IL-1β, IL-6, and TNF-α) in the hippocampus and prefrontal cortex were detected by immunohistochemistry. Inflammatory disorder in the lung, hippocampus, and prefrontal cortex was tested by hematoxylin and eosin (H&E) staining. And cell apoptosis in the hippocampus and prefrontal cortex was measured by TUNEL test. ITGB4^−/− mice exhibited mania-like behavior, including hyperlocomotion, d-amphetamine-induced hyperactivity, and reduced anxiety-like behavior. While under stressful conditions, ITGB4^−/− mice manifested depressive-like behavior, including anhedonia, behavioral despair, and enhanced learned helplessness. At the same time, ITGB4^−/− mice mainly exerted Th2-type inflammation in periphery, like the number and major cytokines IL-4 and IL-13 of Th2-type inflammation. ITGB4^−/− mice also showed a significant increase of microglia and pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α in the hippocampus and prefrontal cortex. Additionally, neuron damage, increased neuron apoptosis, and the decrease of SYP were found in ITGB4^−/− mice. These findings confirmed that airway inflammatory induced by ITGB4 deficiency is the important incentive for the BD-like behavior during asthma pathogenesis. The ITGB4-deficient mice provide a validated animal model for us to study the possible mechanism of BD-like psychiatric comorbidity of asthma patients.

The mortality rate of idiopathic pulmonary fibrosis (IPF) increases yearly due to ineffective treatment. Given that the lung is exposed to the external environment, it is likely that oxidative stress, especially the stimulation of DNA, would be of particular importance in pulmonary fibrosis. DNA damage is known to play an important role in idiopathic pulmonary fibrosis initiation, so DNA repair systems targeting damage are also crucial for the survival of lung cells. Although many contemporary reports have summarized the role of individual DNA damage and repair pathways in their hypotheses, they have not focused on idiopathic pulmonary fibrosis. This review, therefore, aims to provide a concise overview for researchers to understand the pathways of DNA damage and repair and their roles in IPF.

Integrin β4 (ITGβ4) is a class of transmembrane adhesion molecules composed of hemidesmosomes (HDs). Its unique long intracellular domain provides intricate signal transduction functions. These signal transduction effects are especially prominent in tumors. Many recent studies have shown that integrin β4 is differentially expressed in various tumors, and it plays a vital role in tumor invasion, proliferation, epithelial–mesenchymal transition, and angiogenesis. Therefore, we categorize the research related to integrin β4, starting from its structure and function in tumor tissues, and provide a basic description. Based on its structure and function, we believe that integrin β4 can be used as a tumor marker. In clinical practice, it is described as a diagnostic marker for the targeted treatment of cancer and will be helpful in the clinical diagnosis and treatment of tumors.

In the airway, Cl^- is the most abundant anion and is critically involved in transepithelial transport. The correlation of the abnormal expression and activation of chloride channels (CLCs), such as cystic fibrosis transmembrane conductance regulators (CFTRs), anoctamin-1, and CLC-2, with cell migration capability suggests a relationship between defective Cl^- transport and epithelial wound repair. However, whether a correlation exists between intracellular Cl^- and airway wound repair capability has not been explored thus far, and the underlying mechanisms involved in this relationship are not fully defined.

Persistent injury and the following improper repair in bronchial epithelial cells are involved in the pathogenesis of airway inflammation and airway remodeling of asthma. E-cadherin (ECAD) has been shown to be involved in airway epithelium injury repair, but its underlying mechanisms to this process is poorly understood. Here, we describe a previously undetected function of ECAD in regulating the balance of EMT and MET during injury repair. Injury in mice and human bronchial epithelial cells (HBECs) was induced by successive ozone stress for 4 days at 30 min per day. ECAD overexpression in HBECs was induced by stable transfection. EMT features, transforming growth factor beta1 (TGF-β1) secretion, transcriptional repressor Snail expression, and β-catenin expression were assayed. Ozone exposure and then removal successfully induced airway epithelium injury repair during which EMT and MET occurred. The levels of TGF-β1 secretion and Snail expression increased in EMT process and decreased in MET process. While ECAD overexpression repressed EMT features; enhanced MET features; and decreased TGF-β1 secretion, Snail mRNA level, and β-catenin protein expression. Moreover, activating β-catenin blocked the effects of ECAD on EMT, MET and TGF-β1 signaling. Our results demonstrate that ECAD regulates the balance between EMT and MET, by preventing β-catenin to inhibit TGFβ1 and its target genes, and finally facilitates airway epithelia repair.

8‐Oxoguanine DNA glycosylase‐1 (OGG1)‐initiated base excision repair pathway is primarily responsible for 7, 8‐dihydro‐8‐oxoguanine (8‐oxoG) removal from DNA. Recent studies, however, have shown that 8‐oxoG in gene regulatory elements may serve as an epigenetic mark, and OGG1 has distinct functions in modulating gene expression. Genome‐wide mapping of oxidative stress‐induced OGG1 enrichment within introns was documented, but its significance has not yet been fully characterized. Here, we explored whether OGG1 recruited to intron 1 of tissue inhibitor of metalloproteinase‐1 (TIMP1) gene and modulated its expression. Using chromatin and DNA:RNA hybrid immunoprecipitation assays, we report recruitment of OGG1 to the DNA:RNA hybrid in intron 1, where it increases nascent RNA but lowers mRNA levels in O₃‐exposed human airway epithelial cells and mouse lungs. Decrease in TIMP1 expression is alleviated by antioxidant administration, small interfering RNA depletion, or inhibition of OGG1 binding to its genomic substrate. In vitro studies revealed direct interaction between OGG1 and 8‐oxoG containing DNA:RNA hybrid, without excision of its substrate. Inhibition of OGG1 binding to DNA:RNA hybrid translated into an increase in TIMP1 expression and a decrease in oxidant‐induced lung inflammatory responses as well as airway remodeling. Data documented here reveal a novel molecular link between OGG1 at damaged sites and transcription dynamics that may contribute to oxidative stress‐induced cellular and tissue responses.—Pan, L., Wang, H., Luo, J., Zeng J., Pi, J., Liu, H., Liu, C., Ba, X., Qu, X., Xiang Y., Boldogh, I., Qin, X. Epigenetic regulation of TIMP1 expression by 8‐oxoguanine DNA glycosylase‐1 binding to DNA:RNA hybrid. FASEB J. 33, 14159‐14170 (2019). www.fasebj.org