Purpose of Review
Obesity-associated difficult asthma continues to be a substantial problem and, despite a move to address treatable traits affecting asthma morbidity and mortality, it remains poorly ...understood with limited phenotype-specific treatments. The complex association between asthma, obesity, and inflammation is highlighted and recent advances in treatment options explored.
Recent Findings
Obesity negatively impacts asthma outcomes and has a causal link in the pathogenesis of adult-onset asthma. Imbalance in the adipose organ found in obesity favours a pro-inflammatory state both systemically and in airways. Obesity may impact currently available asthma biomarkers, and obesity-associated asthma specific biomarkers are needed. Whilst surgical weight loss interventions are associated with improvements in asthma control and quality of life, evidence for pragmatic conservative options are sparse. Innovative approaches tackling obesity-mediated airway inflammation may provide novel therapies.
Summary
The immunopathological mechanisms underlying obesity-associated asthma require further research that may lead to novel therapeutic options for this disease. However, weight loss appears to be effective in improving asthma in this cohort and focus is also needed on non-surgical treatments applicable in the real-world setting.
We have previously shown that transplantation of autologously derived, respiration-competent mitochondria by direct injection into the heart following transient ischemia and reperfusion enhances cell ...viability and contractile function. To increase the therapeutic potential of this approach, we investigated whether exogenous mitochondria can be effectively delivered through the coronary vasculature to protect the ischemic myocardium and studied the fate of these transplanted organelles in the heart. Langendorff-perfused rabbit hearts were subjected to 30 minutes of ischemia and then reperfused for 10 minutes. Mitochondria were labeled with 18F-rhodamine 6G and iron oxide nanoparticles. The labeled mitochondria were either directly injected into the ischemic region or delivered by vascular perfusion through the coronary arteries at the onset of reperfusion. These hearts were used for positron emission tomography, microcomputed tomography, and magnetic resonance imaging with subsequent microscopic analyses of tissue sections to confirm the uptake and distribution of exogenous mitochondria. Injected mitochondria were localized near the site of delivery; while, vascular perfusion of mitochondria resulted in rapid and extensive dispersal throughout the heart. Both injected and perfused mitochondria were observed in interstitial spaces and were associated with blood vessels and cardiomyocytes. To determine the efficacy of vascular perfusion of mitochondria, an additional group of rabbit hearts were subjected to 30 minutes of regional ischemia and reperfused for 120 minutes. Immediately following regional ischemia, the hearts received unlabeled, autologous mitochondria delivered through the coronary arteries. Autologous mitochondria perfused through the coronary vasculature significantly decreased infarct size and significantly enhanced post-ischemic myocardial function. In conclusion, the delivery of mitochondria through the coronary arteries resulted in their rapid integration and widespread distribution throughout the heart and provided cardioprotection from ischemia-reperfusion injury.
Background Airway inflammation is associated with asthma exacerbation risk, treatment response, and disease mechanisms. Objective This study aimed to identify and validate a sputum gene expression ...signature that discriminates asthma inflammatory phenotypes. Methods An asthma phenotype biomarker discovery study generated gene expression profiles from induced sputum of 47 asthmatic patients. A clinical validation study (n = 59 asthmatic patients) confirmed differential expression of key genes. A 6-gene signature was identified and evaluated for reproducibility (n = 30 asthmatic patients and n = 20 control subjects) and prediction of inhaled corticosteroid (ICS) response (n = 71 asthmatic patients). Receiver operating characteristic curves were calculated, and area under the curve (AUC) values were reported. Results From 277 differentially expressed genes between asthma inflammatory phenotypes, we identified 23 genes that showed highly significant differential expression in both the discovery and validation populations. A signature of 6 genes, including Charcot-Leydon crystal protein (CLC) ; carboxypeptidase A3 (CPA3) ; deoxyribonuclease I-like 3 (DNASE1L3) ; IL-1β (IL1B) ; alkaline phosphatase, tissue-nonspecific isozyme (ALPL) ; and chemokine (C-X-C motif) receptor 2 (CXCR2) , was reproducible and could significantly ( P < .0001) discriminate eosinophilic asthma from other phenotypes, including patients with noneosinophilic asthma (AUC, 89.6%), paucigranulocytic asthma (AUC, 92.6%), or neutrophilic asthma (AUC, 91.4%) and healthy control subjects (AUC, 97.6%), as well as discriminating patients with neutrophilic asthma from those with paucigranulocytic asthma (AUC, 85.7%) and healthy control subjects (AUC, 90.8). The 6-gene signature predicted ICS response (>12% change in FEV1 ; AUC, 91.5%). ICS treatment reduced the expression of CLC , CPA3 , and DNASE1L3 in patients with eosinophilic asthma. Conclusions A sputum gene expression signature of 6 biomarkers reproducibly and significantly discriminates inflammatory phenotypes of asthma and predicts ICS treatment response. This signature has the potential to become a useful diagnostic tool to assist in the clinical diagnosis and management of asthma.
Mitochondrial transplantation is a novel therapeutic intervention to treat ischemia/reperfusion related disorders. The method for mitochondrial transplantation is simple and rapid and can be ...delivered to the end organ either by direct injection or vascular infusion. In this review, we provide mechanistic and histological studies in large animal models and present data to show clinical efficacy in human patients.
Circulating vascular endothelial growth factor (VEGF) ligands and receptors are central regulators of vasculogenesis, angiogenesis, and lymphangiogenesis. In response to VEGF ligand binding, VEGF ...receptor tyrosine kinases initiate the chain of events that transduce extracellular signals into endothelial cell responses such as survival, proliferation, and migration. These events are controlled by intricate cellular processes that include the regulation of gene expression at multiple levels, interactions of numerous proteins, and intracellular trafficking of receptor-ligand complexes. Endocytic uptake and transport of macromolecular complexes through the endosome-lysosome system helps fine-tune endothelial cell responses to VEGF signals. Clathrin-dependent endocytosis remains the best understood means of macromolecular entry into cells, although the importance of non-clathrin-dependent pathways is increasingly recognized. Many of these endocytic events rely on adaptor proteins that coordinate internalization of activated cell-surface receptors. In the endothelium of both blood and lymphatic vessels, epsins 1 and 2 are functionally redundant adaptors involved in receptor endocytosis and intracellular sorting. These proteins are capable of binding both lipids and proteins and are important for promoting curvature of the plasma membrane as well as binding ubiquitinated cargo. Here, we discuss the role of epsin proteins and other endocytic adaptors in governing VEGF signaling in angiogenesis and lymphangiogenesis and discuss their therapeutic potential as molecular targets.
In the past two decades, thousands of non-coding RNAs (ncRNAs) have been discovered, annotated, and characterized in nearly every tissue under both physiological and pathological conditions. Here, we ...will focus on the role of ncRNAs, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) in ischemic heart disease (IHD), which remains the leading cause of morbidity and mortality in humans—resulting in 8.9 million deaths annually. Cardiomyocyte (CM) proliferation, differentiation, and survival in addition to neovascularization of injured tissues and the prevention of fibrosis are commonly regarded as critically important for the recovery of the heart following myocardial infarction (MI). An abundance of evidence has been accumulated to show ncRNAs participate in cardiac recovery after MI. Because miRNAs are important regulators of cardiac regeneration, the therapeutic potential of at least five of these molecules has been assessed in large animal models of human IHD. In particular, miRNA-based interventions based on miR-132 and miR-92a inhibition in related diseases have displayed favorable outcomes that have provided the impetus for miRNA-based clinical trials for IHD. At the same time, the functional roles of lncRNAs and circRNAs in cardiac regeneration are also being explored. In the present review, we will summarize the latest ncRNA studies aimed at reversing damage to the ischemic heart and discuss the therapeutic potential of targeting miRNAs, lncRNAs, and circRNAs to stimulate cardiac regeneration.
Abstract Objective To demonstrate the clinical efficacy of autologous mitochondrial transplantation in preparation for translation to human application using an in vivo swine model. Methods A left ...mini-thoracotomy was performed on Yorkshire pigs. The pectoralis major was dissected, and skeletal muscle tissue was removed and used for the isolation of autologous mitochondria. The heart was subjected to regional ischemia (RI) by temporarily snaring the circumflex artery. After 24 minutes of RI, hearts received 8 × 0.1 mL injections of vehicle (vehicle-only group; n = 6) or vehicle containing mitochondria (mitochondria group; n = 6) into the area at risk (AAR), and the snare was released. The thoracotomy was closed, and the pigs were allowed to recover for 4 weeks. Results Levels of creatine kinase-MB isoenzyme and cardiac troponin I were significantly increased ( P = .006) in the vehicle-only group compared with the mitochondria group. Immune, inflammatory, and cytokine activation markers showed no significant difference between groups. There was no significant between-group difference in the AAR ( P = .48), but infarct size was significantly greater in the vehicle group ( P = .004). Echocardiography showed no significant differences in global function. Histochemistry and transmission electron microscopy revealed damaged heart tissue in the vehicle group that was not apparent in the mitochondria group. T2-weighted magnetic resonance imaging and histology demonstrated that the injected mitochondria were present for 4 weeks. Conclusions Autologous mitochondrial transplantation provides a novel technique to significantly enhance myocardial cell viability following ischemia and reperfusion in the clinically relevant swine model.
Tissue ischemia adversely affects the function of mitochondria, which results in impairment of oxidative phosphorylation and compromised recovery of the affected organ. The impact of ischemia on ...mitochondrial function has been extensively studied in the heart because of the morbidity and mortality associated with injury to this organ. As conventional methods to preserve cardiac cell viability and contractile function following ischemia are limited in their efficacy, we developed a unique approach to protect the heart by transplanting respiration-competent mitochondria to the injured region. Our previous animal experiments showed that transplantation of isolated mitochondria to ischemic heart tissue leads to decreases in cell death, increases in energy production, and improvements in contractile function. We also discovered that exogenously-derived mitochondria injected or perfused into ischemic hearts were rapidly internalised by cardiac cells. Here, we used three-dimensional super-resolution microscopy and transmission electron microscopy to determine the intracellular fate of endocytosed exogenous mitochondria in human iPS-derived cardiomyocytes and primary cardiac fibroblasts. We found isolated mitochondria are incorporated into cardiac cells within minutes and then transported to endosomes and lysosomes. The majority of exogenous mitochondria escape from these compartments and fuse with the endogenous mitochondrial network, while some of these organelles are degraded through hydrolysis.
Mitochondrial damage and dysfunction occur during ischemia and modulate cardiac function and cell survival significantly during reperfusion. We hypothesized that transplantation of autologously ...derived mitochondria immediately prior to reperfusion would ameliorate these effects. New Zealand White rabbits were used for regional ischemia (RI), which was achieved by temporarily snaring the left anterior descending artery for 30 min. Following 29 min of RI, autologously derived mitochondria (RI-mitochondria; 9.7 ± 1.7 × 10(6)/ml) or vehicle alone (RI-vehicle) were injected directly into the RI zone, and the hearts were allowed to recover for 4 wk. Mitochondrial transplantation decreased (P < 0.05) creatine kinase MB, cardiac troponin-I, and apoptosis significantly in the RI zone. Infarct size following 4 wk of recovery was decreased significantly in RI-mitochondria (7.9 ± 2.9%) compared with RI-vehicle (34.2 ± 3.3%, P < 0.05). Serial echocardiograms showed that RI-mitochondria hearts returned to normal contraction within 10 min after reperfusion was started; however, RI-vehicle hearts showed persistent hypokinesia in the RI zone at 4 wk of recovery. Electrocardiogram and optical mapping studies showed that no arrhythmia was associated with autologously derived mitochondrial transplantation. In vivo and in vitro studies show that the transplanted mitochondria are evident in the interstitial spaces and are internalized by cardiomyocytes 2-8 h after transplantation. The transplanted mitochondria enhanced oxygen consumption, high-energy phosphate synthesis, and the induction of cytokine mediators and proteomic pathways that are important in preserving myocardial energetics, cell viability, and enhanced post-infarct cardiac function. Transplantation of autologously derived mitochondria provides a novel technique to protect the heart from ischemia-reperfusion injury.
Transfer RNAs (tRNAs) are abundantly expressed, small non-coding RNAs that have long been recognized as essential components of the protein translation machinery. The tRNA-derived small RNAs ...(tsRNAs), including tRNA halves (tiRNAs), and tRNA fragments (tRFs), were unexpectedly discovered and have been implicated in a variety of important biological functions such as cell proliferation, cell differentiation, and apoptosis. Mechanistically, tsRNAs regulate mRNA destabilization and translation, as well as retro-element reverse transcriptional and post-transcriptional processes. Emerging evidence has shown that tsRNAs are expressed in the heart, and their expression can be induced by pathological stress, such as hypertrophy. Interestingly, cardiac pathophysiological conditions, such as oxidative stress, aging, and metabolic disorders can be viewed as inducers of tsRNA biogenesis, which further highlights the potential involvement of tsRNAs in these conditions. There is increasing enthusiasm for investigating the molecular and biological functions of tsRNAs in the heart and their role in cardiovascular disease. It is anticipated that this new class of small non-coding RNAs will offer new perspectives in understanding disease mechanisms and may provide new therapeutic targets to treat cardiovascular disease.
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