Citations

Abstract Nicotine exposure in the context of smoking or vaping worsens airway function. Although nicotinic acetylcholine receptors (nAChRs) are commonly thought to exert effects through the peripheral nervous system, we previously showed that airway smooth muscle (ASM) expresses them, particularly α7 subtype nAChR (α7nAChR), with functional effects on contractility and metabolism. However, the mechanisms of nAChR regulation and downstream effects in ASM are not fully understood. Using ASM cells from people without asthma versus people with mild to moderate asthma, we tested the hypothesis that nAChR-specific endoplasmic reticulum (ER) chaperones, resistance to inhibitors of cholinesterase 3 (RIC-3) and transmembrane protein 35A (TMEM35A) promote cell surface localization of α7nAChR with downstream influence on its functionality: effects exacerbated by inflammation. We found that mild to moderate asthma and exposure to proinflammatory cytokines relevant to asthma promote chaperone and α7nAChR expression in ASM. Downstream, ER stress was linked to nicotine/α7nAChR signaling, where RIC-3 and TMEM35 regulate nicotine-induced ER stress, intracellular Ca2+ regulation, and ASM cell proliferation. Overall, our data highlight the importance α7nAChR chaperones in mediating and modulating nicotine effects in ASM toward airway contractility and remodeling.

Background: Mycobacterium nebraskense is a rare, slow growing nontuberculous mycobacterium species with limited documented cases. This systematic review aims to comprehensively analyze the clinical characteristics, presentation, and management of M. nebraskense infections by analyzing the available literature, including a newly reported case that we present in this article. Methods: A comprehensive search was conducted using PubMed and Google Scholar to identify relevant cases up to October 2023. Only seven reported cases were found, highlighting the scarcity of information on this pathogen. Results: Our analysis revealed several key findings. First, gender disparities were observed, with females being more susceptible to M. nebraskense infections. Additionally, a significant portion of patients presented with asymptomatic infections. Most affected individuals were over the age of 60, emphasizing potential age-related susceptibility. Comorbidity profiles varied widely among cases, and patients with preexisting lung comorbidities were at an increased risk of infection. The decision to treat or observe depended on clinical presentation, with even immunosuppressed individuals not always requiring treatment. Regarding treatment, we proposed an empirical approach with amikacin, clarithromycin, or rifabutin, considering the reported resistance to doxycycline and minocycline. Combination therapy was commonly employed to minimize resistance development, consistent with mycobacterial infection management. Conclusion: This study underscores the need for further research to validate these findings and enhance our understanding of M. nebraskense infections. As limited data are available, this review aims to provide valuable insights into a rare and emerging pathogen to guide clinical practice and future research endeavors.

ABSTRACTInflammatory cell infiltration is a characteristic feature of COPD and correlates directly with the severity of the disease. Interleukin‐23 (IL‐23) is a pro‐inflammatory cytokine that regulates Th‐17 inflammation, which mediates many pathophysiological events in COPD. The primary goal of this study was to determine the role of IL‐23 as a mediator of key pathologic processes in cigarette smoke‐induced COPD. In this study, we report an increase in IL23 gene expression in the lung biopsies of COPD patients compared to controls and identified a positive correlation between IL23 gene expression and disease severity. In a cigarette smoke‐induced murine emphysema model, the suppression of IL‐23 with a monoclonal blocking antibody reduced the severity of cigarette smoke‐induced murine emphysema. Mechanistically, the suppression of IL‐23 was associated with a reduction in immune cell infiltration, oxidative stress injury, and apoptosis, suggesting a role for IL‐23 as an essential immune mediator of the inflammatory processes in the pathogenesis of CS‐induced emphysema.

The lung is an inherently mechanosensitive organ that can respond to mechanical forces in adaptive or maladaptive ways, including via remodeling resulting in increased fibrosis. We explored the mechanisms that link mechanical forces to remodeling using human lung fibroblasts. We found that mechanosensitive Piezo channels increase with stretch and mediate extracellular matrix formation and the fibroblast-to-myofibroblast transition that occurs with stretch. Our data highlight the importance of Piezo channels in lung mechanotransduction toward remodeling.

Fibrosis in the lung is thought to be driven by epithelial cell dysfunction and aberrant cell-cell interactions. Unveiling the molecular mechanisms of cellular plasticity and cell-cell interactions is imperative to elucidating lung regenerative capacity and aberrant repair in pulmonary fibrosis. By mining publicly available RNA-Seq data sets, we identified loss of CCAAT enhancer-binding protein alpha (CEBPA) as a candidate contributor to idiopathic pulmonary fibrosis (IPF). We used conditional KO mice, scRNA-Seq, lung organoids, small-molecule inhibition, and potentially novel gene manipulation methods to investigate the role of CEBPA in lung fibrosis and repair. Long-term (6 months or more) of Cebpa loss in AT2 cells caused spontaneous fibrosis and increased susceptibility to bleomycin-induced fibrosis. Cebpa knockout (KO) in these mice significantly decreased AT2 cell numbers in the lung and reduced expression of surfactant homeostasis genes, while increasing inflammatory cell recruitment as well as upregulating S100a8/a9 in AT2 cells. In vivo treatment with an S100A8/A9 inhibitor alleviated experimental lung fibrosis. Restoring CEBPA expression in lung organoids ex vivo and during experimental lung fibrosis in vivo rescued CEBPA deficiency–mediated phenotypes. Our study establishes a direct mechanistic link between CEBPA repression, impaired AT2 cell identity, disrupted tissue homeostasis, and lung fibrosis.

AbstractSupplemental O2 (hyperoxia) is a critical intervention for premature infants (<34 weeks) but consequently is associated with development of bronchial airway hyperreactivity (AHR) and asthma. Clinical practice shifted toward the use of moderate hyperoxia (<60% O2), but risk for subsequent airway disease remains. In mouse models of moderate hyperoxia, neonatal mice have increased AHR with effects on airway smooth muscle (ASM), a cell type involved in airway tone, bronchodilation, and remodeling. Understanding mechanisms by which moderate O2 during the perinatal period initiates sustained airway changes is critical to drive therapeutic advancements toward treating airway diseases. We propose that cellular clock factor BMAL1 is functionally important in developing mouse airways. In adult mice, cellular clocks target pathways highly relevant to asthma pathophysiology and Bmal1 deletion increases inflammatory response, worsens lung function, and impacts survival outcomes. Our understanding of BMAL1 in the developing lung is limited, but our previous findings show functional relevance of clocks in human fetal ASM exposed to O2. Here, we characterize Bmal1 in our established mouse neonatal hyperoxia model. Our data show that Bmal1 KO deleteriously impacts the developing lung in the context of O2 and these data highlight the importance of neonatal sex in understanding airway disease.

Bicuspid aortic valve (BAV) is the most common congenital heart malformation in adults, but it can also cause childhood-onset complications. The presentation and clinical course of young adults who present due to BAV complications are relatively uncharacterized. In a multicenter study, we found that young people who experience significant complications related to BAV disease before age 30 are distinguished from the majority of BAV cases that manifest after age 50 by a relatively severe clinical course, with higher rates of surgical interventions, more frequent second interventions, and a greater burden of congenital heart malformations. These observations highlight the need for prompt recognition, regular lifelong surveillance, and targeted interventions to address the significant health burdens of patients with early-onset BAV complications.

Objectives Endovascular aneurysm repair, though minimally invasive and has the benefit of relatively low perioperative complication rates, it is associated with significant long term reintervention rates related to endoleaks. Several variables have been studied to predict the outcomes of endovascular aneurysm repair, 1 of which is the calcium burden of the vasculature. This prompted us to study the association between calcium burden measured by the standardized Agatston scoring system and the outcomes of Endovascular aneurysm repair. Methods This is a retrospective study of patients who underwent Endovascular aneurysm repair from 2008 to 2020 at our institution and who had a non-contrast computerized tomography scan preoperatively, accounting for 87 patients. The calcium burden of the vasculature was measured by the Agatston scoring system allowing for better reproducibility, and the outcome variables included mortality and endoleaks. Results Patients with higher median total calcium scores (≥12966.9) had significantly lesser survival (79.8% vs 52.3% ( P = .002) at five years compared to patients with lower median total calcium score (<12966.9). Also, patients with type 2 endoleaks had higher calcium scores in above the aneurysm level ((1591.2 vs 688.2), P = .05)) compared to patients with no type 2 endoleaks. Conclusion Calcium score assigned using a standardized Agatston scoring system can be used as a predictor of mortality risk assisting in deciding the treatment of choice for patients.

AbstractThe rates of opioid use and opioid related deaths are escalating in the United States. Despite this, evidence-based treatments for Opioid Use Disorder are underutilized. There are three medications FDA approved for treatment of Opioid Use Disorder: Methadone, Buprenorphine, and Naltrexone. This article reviews the history, criteria, and mechanisms associated with Opioid Use Disorder. Pertinent pharmacology considerations, treatment strategies, efficacy, safety, and challenges of Methadone, Buprenorphine, and Naltrexone are outlined. Lastly, a practical decision making algorithm is discussed to address pertinent psychiatric and medical comorbidities when prescribing pharmacology for Opioid Use Disorder.

Accurate assessment of GFR is crucial to guiding drug eligibility, dosing of systemic therapy, and minimizing the risks of both undertreatment and toxicity in patients with cancer. Up to 32% of patients with cancer have baseline CKD, and both malignancy and treatment may cause kidney injury and subsequent CKD. To date, there has been lack of guidance to standardize approaches to GFR estimation in the cancer population. In this two-part statement from the American Society of Onco-Nephrology, we present key messages for estimation of GFR in patients with cancer, including the choice of GFR estimating equation, use of race and body surface area adjustment, and anticancer drug dose-adjustment in the setting of CKD. These key messages are based on a systematic review of studies assessing GFR estimating equations using serum creatinine and cystatin C in patients with cancer, against a measured GFR comparator. The preponderance of current data involving validated GFR estimating equations involves the CKD Epidemiology Collaboration (CKD-EPI) equations, with 2508 patients in whom CKD-EPI using serum creatinine and cystatin C was assessed (eight studies) and 15,349 in whom CKD-EPI with serum creatinine was assessed (22 studies). The former may have improved performance metrics and be less susceptible to shortfalls of eGFR using serum creatinine alone. Since included studies were moderate quality or lower, the American Society of Onco-Nephrology Position Committee rated the certainty of evidence as low. Additional studies are needed to assess the accuracy of other validated eGFR equations in patients with cancer. Given the importance of accurate and timely eGFR assessment, we advocate for the use of validated GFR estimating equations incorporating both serum creatinine and cystatin C in patients with cancer. Measurement of GFR via exogenous filtration markers should be considered in patients with cancer for whom eGFR results in borderline eligibility for therapies or clinical trials.