IL-8-dependent inflammation is a hallmark of host lung innate immunity to bacterial pathogens, yet in many human lung diseases, including chronic obstructive pulmonary disease, bronchiectasis, and pulmonary fibrosis, there are progressive, irreversible, pathological changes associated with elevated levels of IL-8 in the lung. To better understand the duality of IL-8-dependent host immunity to bacterial infection and lung pathology, we expressed human IL-8 transgenically in murine bronchial epithelium, and investigated the impact of overexpression on lung bacterial clearance, host immunity, and lung pathology and function. Persistent IL-8 expression in bronchial epithelium resulted in neutrophilia, neutrophil maturation and activation, and chemotaxis. There was enhanced protection against challenge with Pseudomonas aeruginosa, and significant changes in baseline expression of innate and adaptive immunity transcripts for Ccl5, Tlr6, IL-2, and Tlr1. There was increased expression of Tbet and Foxp3 in response to the Pseudomonas antigen OprF, indicating a regulatory T-cell phenotype. However, this enhanced bacterial immunity came at a high price of progressive lung remodeling, with increased inflammation, mucus hypersecretion, and fibrosis. There was increased expression of Ccl3 and reduced expression of Claudin 18 and F11r, with damage to epithelial organization leading to leaky tight junctions, all of which resulted in impaired lung function with reduced compliance, increased resistance, and bronchial hyperreactivity as measured by whole-body plethysmography. These results show that IL-8 overexpression in the bronchial epithelium benefits lung immunity to bacterial infection, but specifically drives lung damage through persistent inflammation, lung remodeling, and damaged tight junctions, leading to impaired lung function.
Background The Heart Team ( HT ) comprises integrated interdisciplinary decision making. Current guidelines assign a Class Ic recommendation for an HT approach to complex coronary artery disease ( CAD ). However, there remains a paucity of data in regard to hard clinical end points. The aim was to determine characteristics and outcomes in patients with complex CAD following HT discussion. Methods and Results This observational study was conducted at St Thomas’ Hospital (London, UK). Case mixture included unprotected left main, 2‐vessel (including proximal left anterior descending artery) CAD , 3‐vessel CAD , or anatomical and/or clinical equipoise. HT strategy was defined as optimal medical therapy ( OMT ) alone, OMT +percutaneous coronary intervention ( PCI ), or OMT +coronary artery bypass grafting. From April 2012 to 2013, 51 HT meetings were held and 398 cases were discussed. Patients tended to have multivessel CAD (74.1%), high SYNTAX (Synergy between PCI with Taxus and Cardiac Surgery) scores (median, 30; interquartile range, 23–39), and average age 69±11 years. Multinomial logistic regression analysis performed to determine variables associated with HT strategy demonstrated decreased likelihood of undergoing PCI compared with OMT in older patients with chronic kidney disease and peripheral vascular disease. The odds of undergoing coronary artery bypass grafting compared with OMT decreased in the presence of cardiogenic shock and left ventricular dysfunction and increased in younger patients with 3‐vessel CAD . Three‐year survival was 60.8% (84 of 137) in the OMT cohort, 84.3% (107 of 127) in the OMT + PCI cohort, and 90.2% in the OMT +coronary artery bypass grafting cohort (92 of 102). Conclusions In our experience, the HT approach involved a careful selection process resulting in appropriate patient‐specific decision making and good long‐term outcomes in patients with complex CAD .
Background AF ablation ( AFA ) with pulmonary vein isolation ( PVI ) is highly successful for paroxysmal atrial fibrillation ( PAF ). However, success rates for persistent AF (Ps AF ) are significantly lower. In this study we evaluate the impact of left atrial ( LA ) low voltage areas ( LVA ) on response to AFA . Methods Consecutive patients undergoing first‐time radiofrequency AFA were included (n = 160, 53% PAF ). PVI was performed followed by LA voltage mapping during sinus rhythm. Patients were categorized as having LVA based on the presence of LVA (0.2‐0.5 mV) in the LA assessed visually by the operator intra‐procedurally. Further adjunctive LA ablation was performed at the operators’ discretion. The end‐point was recurrence of any sustained atrial arrhythmia (atrial fibrillation/tachycardia/flutter) during 12 months follow‐up. Results All patients had PVI and 23 (14%) had adjunctive LA ablation. LVA were found in 49 (31%) patients and were an independent predictor of arrhythmia recurrence. Patients with LVA compared to those without had significantly lower 12‐month arrhythmia‐free survival in both PAF (38% vs 76%; P = 0.002) and Ps AF (27% vs 61%; P = 0.015). Ps AF patients without LVA (93% had PVI alone) had similar arrhythmia‐free survival to patients with PAF (61% vs 67%, respectively; P = 0.42). Recurrence in patients with LVA compared to those without was more likely to be an organized atrial arrhythmia rather than AF (16/30 recurrences vs 2/26, P < 0.001). Conclusions The presence of LVA predicts AFA success as well as the type of arrhythmia recurrence. The absence of LVA identifies Ps AF patients that respond well to a PVI ‐based ablation strategy.
Vascular myocytes are central to brain aging. Small vessel disease (SVD; arteriolosclerosis) is a widespread cause of lacunar stroke and vascular dementia, and is characterised by fibrosis and depletion of vascular myocytes in small penetrating arteries. Vascular endothelial growth factor (VEGF) is associated with brain aging, and VEGFR2 is a potent determinant of cell fate. Here, we tested whether VEGFR2 in vascular myocytes is associated with older age and SVD in human brain.VEGFR2 immunolabelling in deep grey matter was assessed in older people with or without moderate-severe SVD, or in younger people without brain pathology or with a monogenic form of SVD (CADASIL). All cases were without Alzheimer's disease pathology. Myocyte VEGFR2 was associated with increasing age (p=0.0026) but not with SVD pathology or with sclerotic index or blood vessel density. We conclude that VEGFR2 is consistently expressed in small artery myocytes of older people, and may mediate effects of VEGF on brain vascular aging.[word count: 156; <170]
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.