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Renin-angiotensin system blockade: A novel therapeutic approach in chronic obstructive pulmonary disease
Abstract and Figures
ACE (angiotensin-converting enzyme) inhibitors and ARBs (angiotensin II receptor blockers) are already widely used for the treatment and prevention of cardiovascular disease and their potential role in other disease states has become increasingly recognized. COPD (chronic obstructive pulmonary disease) is characterized by pathological inflammatory processes involving the lung parenchyma, airways and vascular bed. The aim of the present review is to outline the role of the RAS (renin-angiotensin system) in the pathogenesis of COPD, including reference to results from fibrotic lung conditions and pulmonary hypertension. The review will, in particular, address the emerging evidence that ACE inhibition could have a beneficial effect on skeletal muscle function and cardiovascular co-morbidity in COPD patients. The evidence to support the effect of RAS blockade as a novel therapeutic approach in COPD will be discussed.
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... AngII, the primary hormone of the RA system, binds to type 1 (AGTR1) and type 2 (AGTR2) AngII receptors 6 , of which AGTR1 mediates the majority of the pathological effects of AngII 6 . The RA system has been implicated in TS-induced pulmonary disorders and lung cancer [6][7][8] . AngII/AGTR1 signaling was found to increase blood flow to tumors by inducing vascular endothelial growth factor (VEGF) release 7 and activating c-Src 7 and insulin-like growth factor 1 receptor (IGF-1R) 9 , key molecules involved in signaling pathways for cellular transformation and survival 10 . ...
... Deregulation of the RA system has been implicated in pulmonary hypertension and inflammation, which mediates the onset of disorders associated with TS, such as chronic obstructive pulmonary disease (COPD) 8 . Epidemiological studies have shown that COPD is an independent risk factor for lung cancer 56,57 , and the use of ACE inhibitors or ARBs reduces the risks of COPD 58 and lung cancer 59 . ...
The renin-angiotensin (RA) system has been implicated in lung tumorigenesis without detailed mechanistic elucidation. Here, we demonstrate that exposure to the representative tobacco-specific carcinogen nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) promotes lung tumorigenesis through deregulation of the pulmonary RA system. Mechanistically, NNK binding to the nicotinic acetylcholine receptor (nAChR) induces Src-mediated signal transducer and activator of transcription 3 (STAT3) activation, resulting in transcriptional upregulation of angiotensinogen (AGT) and subsequent induction of the angiotensin II (AngII) receptor type 1 (AGTR1) signaling pathway. In parallel, NNK concurrently increases insulin-like growth factor 2 (IGF2) production and activation of IGF-1R/insulin receptor (IR) signaling via a two-step pathway involving transcriptional upregulation of IGF2 through STAT3 activation and enhanced secretion from intracellular storage through AngII/AGTR1/PLC-intervened calcium release. NNK-mediated crosstalk between IGF-1R/IR and AGTR1 signaling promoted tumorigenic activity in lung epithelial and stromal cells. Lung tumorigenesis caused by NNK exposure or alveolar type 2 cell-specific Src activation was suppressed by heterozygous Agt knockout or clinically available inhibitors of the nAChR/Src or AngII/AGTR1 pathways. These results demonstrate that NNK-induced stimulation of the lung RA system leads to IGF2-mediated IGF-1R/IR signaling activation in lung epithelial and stromal cells, resulting in lung tumorigenesis in smokers.
... disorders 9 , such as acute lung injury 10,11 , idiopathic pulmonary fibrosis (IPF) 12 , pulmonary hypertension 13,14 , and chronic obstructive pulmonary disease (COPD)-emphysema 15,16 . Since the SARS-CoV-2 receptor (ACE-2) is an angiotensin-processing enzyme, recent clinical studies have even examined the role of this pathway in COVID-19 pathogenesis 17,18 . ...
The renin-angiotensin system is a highly characterized integrative pathway in mammalian homeostasis whose clinical spectrum has been expanded to lung disorders such as chronic obstructive pulmonary disease (COPD)-emphysema, idiopathic pulmonary fibrosis (IPF), and COVID pathogenesis. Despite this widespread interest, specific localization of this receptor family in the mammalian lung is limited, partially due to the imprecision of available antibody reagents. In this study, we establish the expression pattern of the two predominant angiotensin receptors in the human lung, AGTR1 and AGTR2 , using complementary and comprehensive bulk and single-cell RNA-sequence datasets that are publicly available. We show these two receptors have distinct localization patterns and developmental trajectories in the human lung, pericytes for AGTR1 and a subtype of alveolar epithelial type 2 cells for AGTR2 . In the context of disease, we further pinpoint AGTR2 localization to the COPD-associated subpopulation of alveolar epithelial type 2 (AT2 B ) and AGTR1 localization to fibroblasts, where their expression is upregulated in individuals with COPD, but not in individuals with IPF. Finally, we examine the genetic variation of the angiotensin receptors, finding AGTR2 associated with lung phenotype (i.e., cystic fibrosis) via rs1403543. Together, our findings provide a critical foundation for delineating this pathway’s role in lung homeostasis and constructing rational approaches for targeting specific lung disorders.
... Angiotensin-(1-7), converted from Ang II by ACE and ACE2, has been reported to counteract the function of Ang II in many aspects, serving as a biologically active intermediate of the vasodilatory arm of the renin-angiotensin system [4]. RAS plays a pivotal role in the maintenance of normal physiological state in the human body, whose dysregulation has been reported to lead to the onset of various diseases, such as hypertension [5], diabetes [5], stroke [6], chronic obstructive pulmonary disease (COPD) [7], cancer [8], etc. ...
Renin-Angiotensin System (RAS) is a vital system regulating blood pressure and maintaining sodium homeostasis in the human body. It consists of Angiotensin I (Ang I), Angiotensin II (Ang II), Angiotensin-converting enzyme (ACE), Angiotensin II type 1 receptor (AT1R), and angiotensin II type 2 receptor (AT2R), which functions in both normal and pathological conditions including cancer. Besides, the effectors of RAS are also included, such as Angiotensin-(1-7). This review focuses on the pre-clinical studies and clinical trials assessing the roles of RAS in regulating tumor progression as well as the underlying mechanisms.KeywordsRenin-angiotensin systemCancer progressionProliferationAngiogenesisMetastasis
... 6 More specifically, the system affects the development of pulmonary fibrosis, pulmonary hypertension and skeletal muscle dysfunction, which are all observed in COPD. [6][7][8][9] WHAT IS ALREADY KNOWN ON THIS TOPIC ⇒ The renin-angiotensin system (RAS) has been shown to play a role in the pathogenesis of chronic obstructive pulmonary disease (COPD) because of the inflammatory properties of the system. Yet, the association between the use of RAS acting agents and the risk of severe exacerbations has not previously been systematically explored in patients with severe/very severe COPD. ...
Objective
The renin–angiotensin system (RAS) has been shown to play a role in the pathogenesis of chronic obstructive pulmonary disease (COPD) because of the inflammatory properties of the system. Many patients with COPD use RAS-inhibiting (RASi) treatment. The aim was to determine the association between treatment with RASi and the risk of acute exacerbations and mortality in patients with severe COPD.
Methods
Active comparator analysis by propensity-score matching. Data were collected in Danish national registries, containing complete information on health data, prescriptions, hospital admissions and outpatient clinic visits. Patients with COPD (n=38 862) were matched by propensity score on known predictors of the outcome. One group was exposed to RASi treatment (cases) and the other was exposed to bendroflumethiazide as an active comparator in the primary analysis.
Results
The use of RASi was associated with a reduced risk of exacerbations or death in the active comparator analysis at 12 months follow-up (HR 0.86, 95% CI 0.78 to 0.95). Similar results were evident in a sensitivity analysis of the propensity-score-matched population (HR 0.89, 95% CI 0.83 to 0.94) and in an adjusted Cox proportional hazards model (HR 0.93, 95% CI 0.89 to 0.98).
Conclusion
In the current study, we found that the use of RASi treatment was associated with a consistently lower risk of acute exacerbations and death in patients with COPD. Explanations to these findings include real effect, uncontrolled biases, and—less likely—chance findings.
... The renin-angiotensin-aldosterone system (RAAS) is a blood pressure regulating system produced by the kidneys in the body, causing vascular smooth muscle contraction and water and sodium retention, resulting in a blood pressure boosting effect. Renin-angiotensin-aldosterone system inhibitors, including angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARBs), are currently widely used in the prevention and treatment of cardiovascular diseases, while RAAS may promote the progression of COPD and pulmonary fibrosis by inducing the production and release of inflammatory factors and reactive oxygen species (104). There are relatively few data on the application of RAAS inhibitors in patients with COPD. ...
Chronic obstructive pulmonary disease (COPD) is a disease characterized by persistent airflow limitation, and is associated with abnormal inflammatory responses in the lungs to cigarette smoke and toxic and harmful gases. Due to the existence of common risk factors, COPD is prone to multiple complications, among which cardiovascular disease (CVD) is the most common. It is currently established that cardiovascular comorbidities increase the risk of exacerbations and mortality from COPD. COPD is also an independent risk factor for CVD, and its specific mechanism is still unclear, which may be related to chronic systemic inflammation, oxidative stress, and vascular dysfunction. There is evidence that chronic inflammation of the airways can lead to destruction of the lung parenchyma and decreased lung function. Inflammatory cells in the airways also generate reactive oxygen species in the lungs, and reactive oxygen species further promote lung inflammation through signal transduction and other pathways. Inflammatory mediators circulate from the lungs to the whole body, causing intravascular dysfunction, promoting the formation and rupture of atherosclerotic plaques, and ultimately leading to the occurrence and development of CVD. This article reviews the pathophysiological mechanisms of COPD complicated by CVD and the effects of common cardiovascular drugs on COPD.
... 82 AngII may thus contribute to the development and progression of lung inflammation and fibrosis associated with COPD and losartan -an AT1 blocker can inhibit some aspects of lung injury. 79,83 ACEIs or ARBs can improve histological appearances, lung compliance, exercise capacity, and reduce lung fibrosis in animal models of pulmonary disease. [84][85][86] Retrospective data suggest that patients with COPD who either take an ACEI or ARB have slower decline in lung function, 87 and slower progression of emphysematous changes on computed tomography than those that do not. ...
Heart failure (HF) and chronic obstructive pulmonary disease (COPD) are common causes of breathlessness which frequently co-exist; one potentially exacerbating the other. Distinguishing between the two can be challenging due to their similar symptomatology and overlapping risk factors, but a timely and correct diagnosis is potentially lifesaving. Modern treatment for HF can substantially improve symptoms and prognosis for many patients and may have beneficial effects for patients with COPD. Conversely, while many inhaled treatments for COPD can improve symptoms and reduce exacerbations, there is conflicting evidence regarding the safety of some inhaled treatments for COPD in patients with HF. Here we explore the overlap between HF and COPD, examine the effect of one condition on the other, and address the challenges of managing patients with both conditions.
Создание руководства поддержано Советом по терапевтическим наукам отделения клинической медицины Российской академии наук.
Comorbidities are common in chronic obstructive pulmonary disease (COPD). Cardiovascular comorbidity is a leading cause of morbidity and mortality in COPD patients. Low lung function is a risk factor for increased arterial stiffness, a condition that is common in COPD patients, independent of conventional cardiovascular risk factors. Arterial stiffness is an independent risk factor both for all-cause and for cardiovascular mortality, and carotid–femoral pulse wave velocity is the gold standard for the assessment of arterial stiffness. Various mechanisms proposed in the development of arterial stiffness include systemic inflammation, ageing, advanced glycation end products, renin–angiotensin–aldosterone system, increased elastolysis, and vitamin D deficiency. Early detection of arterial stiffness in COPD patients is warranted to detect cardiovascular comorbidity at the subclinical stage, which would help to prevent overt vascular events in the future. We need well-designed studies to see the impact of therapy that targets increased arterial stiffness on future cardiovascular events in COPD. This review discusses the epidemiology, diagnosis, and therapy of increased arterial stiffness in COPD patients.
Angiotensin-converting enzyme in human skeletal muscle1 can be encoded by either of two variants of the ACE gene2, one of which carries an insertion of 287 base pairs. This longer allele gives rise to lower enzyme activity2, and is associated with enhanced endurance performance3 and an anabolic response to intense exercise training4. Here we examine training-related changes in the mechanical efficiency of human skeletal muscle (energy used per unit power output) and find that the presence of this ACE allele confers an enhanced mechanical efficiency in trained muscle.
Chronic obstructive pulmonary disease (COPD) is primarily a lung disease. However, it has important systemic manifestations that include systemic muscle dysfunction. The mechanisms by which muscle dysfunction occurs in COPD remains a matter of debate but includes; disuse atrophy, local response to a systemic inflammatory state, local inflammation, poor energy delivery and use and accelerated damage with poor repair. This monograph reviews our current knowledge of peripheral muscle dysfunction and its mechanisms. It contains a specific review of structure and function and it expands on the relationship of peripheral muscle dysfunction and training as a way to reverse the problem. This field is bound to become a fertile ground for research. Novel therapeutic interventions may offer patients with COPD the opportunity to improve in domains different from airflow limitation, with all gains that may stem from this improvement.
Reactive oxygen species (ROS) cause alterations in the cellular redox status (GSH/GSSG ratio) and hence activate various kinase signaling pathways, redox sensitive transcription factors (NF-κB and AP-1), and chromatin modification enzymes leading to increased pro-inflammatory and immunological responses. Chromatin modification enzymes include histone acetyltransferases (HATs), histone and non-histone deacetylases (HDACs, sirtuins), histone methyltransferases (HMTs) and histone demethylases (HDMs). Activation of these enzymes results in transcriptional gene activation/repression. Histone methyltransferases are enzymes that dynamically cause histone mono-, di- or tri-methylation at lysine residues, which either result in gene activation (H3K4, H3K36, and H3K79) or repression (H3K9, H3K27, and H3K20). Histone demethylases catalyze the removal of methyl groups from lysine or arginine residue of histones, hence regulating gene expression. Recent evidences have indicated that oxidative stress and environmental agents can alter nuclear histone acetylation/deacetylation/methylation, allowing access for transcription factor DNA binding and leading to enhanced pro-inflammatory gene expression. Cross-talks between histone modifications and DNA methylation also occur during inflammation. Understanding the mechanisms of ROS and redox epigenetic regulation via stress signaling kinases, redox sensitive transcription factors, the balance between histone acetylation/deacetylation and histone methylation/demethylation may lead to the development of novel therapies based on epigenetics against chronic inflammatory diseases, and cancer.
Although cytokine-induced nuclear factor κB (NF-κB) pathways are involved in muscle wasting subsequent to disease, their potential role in disuse muscle atrophy has not been characterized. Seven days of hind limb unloading led to a 10-fold activation of an NF-κB-dependent reporter in rat soleus muscle but not the atrophy-resistant extensor digitorum longus muscle. Nuclear levels of p50 were markedly up-regulated, c-Rel was moderately up-regulated, Rel B was down-regulated, and p52 and p65 were unchanged in unloaded solei. The nuclear IκB protein Bcl-3 was increased. There was increased binding to an NF-κB consensus oligonucleotide, and this complex bound antibodies to p50, c-Rel, and Bcl-3 but not other NF-κB family members. Tumor necrosis factor alpha (TNF-α) and TNF receptor-associated factor 2 protein were moderately down-regulated. There was no difference in p38, c-Jun NH2-terminal kinase or Akt activity, nor were activator protein 1 or nuclear factor of activated T cell-dependent reporters activated. Thus, whereas several NF-κB family members are up-regulated, the prototypical markers of cytokine-induced activation of NF-κB seen with disease-related wasting are not evident during disuse atrophy. Levels of an anti-apoptotic NF-κB target, Bcl-2, were increased fourfold whereas proapoptotic proteins Bax and Bak decreased. The evidence presented here suggests that disuse muscle atrophy is associated with activation of an alternative NF-κB pathway that involves the activation of p50 but not p65.—Hunter, R. B., Stevenson, E. J., Koncarevic, A., Mitchell-Felton, H., Essig, D. A., Kandarian, S. C. Activation of an alternative NF-κB pathway in skeletal muscle during disuse atrophy.
One of the most important health achievements during the twentieth century was the unravelling of the causes of the cardiovascular diseases (CVDs). Since the 1980s, coronary artery disease (CAD) mortality rates have been reduced in many developed countries and have fallen by 75% in countries such as Finland.1 Modern cardiovascular treatment has played an important role. The explosion in evidence-based treatments since the 1980s has provided us with the tools to increase life expectancy in those affected by the disease. The discovery of angiotensin-converting enzyme (ACE) inhibitors is one of these important tools. Ironically, ACE inhibitors come from the veins of poisonous snakes and yet their widespread use has saved millions of patients. Again, ironically, ACEs and the renin–angiotensin system have been and still are phylogenetically pivotal for the preservation of the species and for our daily life. The endpoint of the system is the production of angiotensin II, a potent vasoconstrictor and a growth factor essential to counteract bleeding and to repair the eventual hole in the vessel wall. Indeed, bleeding is a threat to mammalian survival and was a threat to primitive man, who was obliged to hunt to survive and therefore exposed to the risk of massive bleeding. Things have, however, changed. With evolution, hunting is often criticized as a sport rather than a necessity and bleeding is no longer a problem during our daily life. Once again, ironically, it is our very high standard of living and lifestyle that is the problem. Several attitudes, generally recognized as risk factors, through several complicated pathways, lead to hypertension and atherosclerosis and start a pernicious continuum of cardiovascular diseases. The primum movens …
*Corresponding author. E-mail address : fri{at}unife.it
Recent work from this laboratory demonstrated that apoptosis of pulmonary alveolar epithelial cells (AEC) in response to fas requires angiotensin II (ANGII) generation de novo and binding to its receptor (Wang et at., 1999b, Am I Physiol Lung Cell Mol Physiol 277:L1245-L1250). These findings led us to hypothesize that a similar mechanism might be involved in the induction of AEC apoptosis by TNF-alpha. Apoptosis was detected by assessment of nuclear and chromatin morphology, increased activity of caspase 3, binding of annexin V, and by net cell loss inhibitable by the caspase inhibitor ZVAD-fmk. Purified human TNF-alpha induced dose-dependent apoptosis in primary type II pneumocytes isolated from rats or in the AEC-derived human lung carcinoma cell line A549. Apoptosis in response to TNF-alpha was inhibited in a dose-dependent manner by the nonselective ANGII receptor antagonist saralasin or by the nonthiol ACE inhibitor lisinopril; the inhibition of TNF-induced apoptosis was maximal at 50 mu g/ml saralasin (101% inhibition) and at 0.5 mu g/ml lisinopril (86% inhibition). in both cell culture models, purified TNF-alpha caused a significant increase in the mRNA for angiotensinogen (ANGEN), which was not expressed in unactivated cells. Transfection of primary cultures of rat AEC with antisense oligonucleotides against ANGEN mRNA inhibited the subsequent induction of TNF-stimulated apoptosis by 72% (P < 0.01). Exposure to TNF-alpha increased the concentration of ANGII in the serum-free extracellular medium by fivefold in A549 cell cultures and by 40-fold in primary AEC preparations; further, exposure to TNF-alpha for 40 h caused a net eel I loss of 70%, which was completely abrogated by either the caspase inhibitor ZVAD-fmk, lisinopril, or saralasin. Apoptosis in response to TNF-alpha was also completely inhibited by neutralizing antibodies specific for ANGII (P < 0.01), but isotype-matched nonimmune immunoglobulins had no significant effect. These data indicate that the induction of AEC apoptosis by TNF-alpha requires a functional renin/angiotensin system (RAS) in the target cell. They also suggest that therapeutic control of AEC apoptosis in response to TNF-alpha is feasible through pharmacologic manipulation of the local RAS. (C) 2000 Wiley-Liss, Inc.
Objectives
The purpose of this study was to determine if statins (hydroxymethylglutaryl CoA reductase inhibitors [HMG-CoA]), angiotensin-converting enzyme (ACE) inhibitors, and angiotensin receptor blockers (ARBs) reduce cardiovascular (CV) events and pulmonary morbidity in chronic obstructive pulmonary disease (COPD) patients.Background
Few current COPD therapies alter prognosis. Although statins, ACE inhibitors, and ARBs improve outcomes in CV populations, their benefits in COPD patients both with and without concomitant heart disease has not previously been studied.MethodsA time-matched nested case-control study of two population-based retrospective cohorts was undertaken: 1) COPD patients having undergone coronary revascularization (high CV risk cohort); and 2) COPD patients without previous myocardial infarction (MI) and newly treated with nonsteroidal anti-inflammatory drugs (low CV risk cohort). Prespecified outcomes were COPD hospitalization, MI, and total mortality.ResultsThese drugs reduced both CV and pulmonary outcomes, with the largest benefits occurring with the combination of statins and either ACE inhibitors or ARBs. This combination was associated with a reduction in COPD hospitalization (risk ratio [RR] 0.66, 95% confidence interval [CI] 0.51 to 0.85) and total mortality (RR 0.42, 95% CI 0.33 to 0.52) not only in the high CV risk cohort but also in the low CV risk cohort (RR 0.77, 95% CI 0.67 to 0.87, and RR 0.36, 95% CI 0.28 to 0.45, respectively). The combination also reduced MI in the high CV risk cohort (RR 0.39, 95% CI 0.31 to 0.49). Benefits were similar when steroid users were included.Conclusions
These agents may have dual cardiopulmonary protective properties, thereby substantially altering prognosis of patients with COPD. These findings need confirmation in randomized clinical trials.