Angiotensin Converting Enzyme Inhibitors and Angiotensin Receptor Blockers: A Promising Medication for Chronic Obstructive Pulmonary Disease?

ABSTRACT

Chronic obstructive pulmonary disease (COPD) is a complex disorder that primarily affects the lungs and is characterized not only by local pulmonary, but also by systemic inflammation which promotes the development of extrapulmonary and cardiovascular co-morbidities. Angiotensin converting enzyme (ACE) inhibitors and ARBs (angiotensin receptor blockers) are widely used drugs in the treatment of cardiovascular diseases, with growing evidence suggesting potential benefits in COPD patients. The purpose of this review is to describe the correlation of renin–angiotensin system (RAS) with COPD pathophysiology and to present the latest data regarding the potential role of RAS blockers in COPD.

KEYWORDS:

• Angiotensin converting enzyme inhibitor
• angiotensin receptor blocker
• chronic obstructive pulmonary disease
• renin-angiotensin system

Introduction

COPD is an underdiagnosed, life-threatening lung disease characterized by chronic obstruction of lung airflow that interferes with normal breathing (1). Tobacco smoke is a key factor in the development and progression of COPD, but exposure to air pollutants, genetic factors and respiratory infections also play a role (1). WHO (World Health Organization) projections suggest that by 2020 COPD will be the 3rd leading cause of death causing 6 million deaths annually worldwide (1, 2).

From the pathophysiological point of view, COPD is a progressive inflammatory disease of the airways, the alveoli, and the microvasculature (1). In addition to lung inflammation, chronic systemic inflammation also occurs, classifying COPD as a multisystemic disorder (3) Recognized systemic consequences of COPD include cardiovascular disease, diabetes mellitus, malnutrition, muscle dysfunction, lung cancer, osteoporosis, infections, anemia and depression (3, 4). RAS has been shown to be implicated in the pathogenesis of pulmonary and extra-pulmonary manifestations of COPD. This review presents the pathophysiological correlation of RAS and COPD, and highlights the potential therapeutic benefit of RAS blockade in COPD patients.

Pathophysiological correlation of RAS and COPD

A local RAS exists in many human tissues, including lung and skeletal muscle (5). The participation of renin in angiotensinogen conversion into angiotensin I (Ang I) is the first part of the activation of the RAS (5). ACE is an enzyme present in the circulating plasma and highly expressed in lung capillary blood vessels, which catalyzes the conversion of Ang I to Ang II (5). Ang II stimulates aldosterone synthesis from the adrenal cortex (5). Aldosterone then acts on renal tubules to promote salt/water retention (5). This hormonal pathway enables ACE to regulate sodium and water balance and vascular resistance (5). Additionally, ACE is involved in the cleavage of bradykinin, which when active, can mediate the release of nitric oxide (NO) and prostaglandins (5). A schematic presentation of RAS system is shown in Figure 1.

Figure 1. The renin-angiotensin-aldosterone system.

Ang II exerts its effects primarily by binding to and activating AT1 (Ang II type 1) and AT2 (Ang II type 2) receptors to modulate vascular tone (6). Activation of AT1 receptors initiates a vasoconstrictor response whereas activation of AT2 receptors promotes local vasodilation (7). The AT1/AT2 receptor ratio increases noticeably in regions of marked fibrosis surrounding bronchioles, which correlates with the reduction in forced expiratory volume in 1 s (FEV1) (8). These actions support a role for angiotensin II in inducing bronchoconstriction via the AT1 receptor (8).

In addition to Ang II, other recently identified end-products of the RAS system, include Angiotensin-(1-7) [Ang-(1-7)], Ang-(1-9), Ang-(1-5), Ang A, Ang III, Ang IV, and alamandine (9, 10). These novel components of RAS, especially Ang-(1-7), interfere with the development of COPD (11, 12). In particular, the detrimental effects of angiotensin II in the cardiopulmonary system are counterbalanced by its catabolism via angiotensin converting enzyme-2 (ACE-2).^13-15ACE-2 is a homologue of ACE, insensitive to ACE inhibitors, which hydrolyzes either Ang I or Ang II into [Ang-(1-7)], [Ang-(1-9)], [Ang-(1-5)] (10). Ang-(1-7) can also be generated directly from Ang I through the actions of other enzymes (16). Ang-(1-7) acts through the Mas receptor (MasR) to mediate anti-proliferative, anti-fibrotic, and anti-inflammatory effects (16, 17). The benefits of ACE-2 on heart and lungs are mediated by a reduction in Ang II and elevation in Ang-(1-7) levels (17). It is generally believed that a balance exists between Ang II and Ang-(1-7), which supports cardiopulmonary homeostasis. Upregulation of Ang II leads to vasoconstriction, hypertrophy, proliferation, inflammation and fibrosis, all factors that contribute to the development of cardiopulmonary diseases (17). On the contrary, stimulation of Ang-(1-7) inhibits many pathways through which Ang II acts, limits proliferation and maintains pulmonary vascular cell homeostasis, mediating valuable effects on heart and lungs (17–19). Recent data suggest that ACE-2 demonstrates a protective role in pulmonary function and that therapeutic approaches targeting this enzyme might be effective in ameliorating lung injury (20–22).

RAS also seems to be implicated in the pathogenesis of COPD through stimulation of proinflammatory mediators in the lung, such us interleukin-6 (IL-6) and tumor necrosis factor-a (TNF-a) (23–25). Moreover, it has an immunomodulatory effect on T-cell responses, which mediate lung tissue injury associated with COPD (23–25).

The RAS can also generate reactive oxygen species via AT1 receptors, thereby promoting mitochondrial dysfunction, which contributes to oxidative stress and endothelial dysfunction observed in patients with COPD (26, 27). The actions of the RAS in COPD are schematically presented in Figure 2.

Figure 2. Actions of RAS in COPD. (Lines ending with a perpendicular segment represent inhibitory pathways).

Pulmonary fibrosis

Pulmonary fibrosis is a key component of airway remodeling in COPD (28, 29). RAS is activated after lung injury by a variety of endogenous and xenobiotic agents to promote tissue repair and when in excess, tissue fibrosis (30). Ang II is the main facilitator of these fibrous processes as it induces growth factors for mesenchymal cells, promotes extracellular matrix synthesis and induces fibroblast proliferation and modification of their mechanical characteristics (30). Evidence for involvement of the pulmonary RAS in lung fibrosis comes from genetic studies of RAS gene polymorphisms in patients with lung fibrosis, demonstrations of activated RAS genes and protein products in lung biopsy specimens from patients with lung fibrosis and a variety of animal model studies (30). First, Ang II is mitogenic for human lung fibroblasts through AT1 and AT2 receptors (31, 32). It has been shown that both AT1 and AT2 receptors mediate Ang II effects on fibroblast cell cycle and migration via phosphorylation of the mitogen-activated protein kinases p38 and p42/44 (31, 32). In addition, Ang II promotes extracellular matrix (ECM) synthesis in human lung fibroblasts (32, 33). Type I collagen is a principal matrix protein in the lung interstitium. Excessive collagen type I, mainly synthesized by activated fibroblasts, has been largely recognized in the pathogenesis of fibrosis and causes thickened alveolar walls and reduced lung compliance (33). ECM synthesis mediated by Ang II has been ascribed not only to AT1 receptor activation but also to the autocrine action of transforming growth factor-β1 (TGF-β1) (32, 33) and connective tissue growth factor (CTGF) (34). Both growth factors contribute to the development of lung fibrosis enhancing human lung fibroblast differentiation to myofibroblasts and stimulating collagen synthesis (34, 35). In vitro studies have demonstrated that these pro-fibrotic effects induced by TGF-β1 and CTGF, as well as the collagen synthesis triggered by oxidant stress, are abrogated through the blockade of angiotensin receptors (32, 33, 35). On the other hand, transcriptional regulation and autocrine loop systems are believed to be involved in the molecular mechanisms by which Ang II exerts its functions in lung fibrosis. For example, an Ang II-TGF-β1 crosstalk has been identified in lung fibroblasts isolated from fibrotic human lung (33). The transition to the myofibroblast phenotype induced by TGF-β1 increases AGT and AT1 receptor expression (33, 34, 36). Uhal et al. reported that constitutive expression of active TGF-β1 by human lung myofibroblasts was downregulated by Ang II receptor blockade and was accompanied by the inhibition of collagen synthesis (33). In the same vein, Renzoni et al. described an additional effect of Ang II on ECM and human lung fibroblast cells (36). They observed that the increased contractility of lung fibroblasts isolated from fibrotic lungs is dependent on angiotensin signaling (36). Consequently, in addition to exerting the mitogenic and regulatory effects, Ang II can also modify cytoskeletal function and the mechanical characteristics of human lung fibroblasts (36). In animal models, administration of ACE inhibitors has led to attenuation of experimental pulmonary fibrosis (37-41).

As for the ACE-2/Ang-(1-7) axis, it appears to possess potent anti-fibrotic properties (30). Several studies show that ACE-2 expression is downregulated in human and animal models of pulmonary fibrosis (42–44). The impact of ACE inhibitors and ARBs on oxidative stress, proinflammatory signaling and proliferative effects induced by RAS activation is shown in Figure 3.

Figure 3. Impact of ACE inhibitors and ARBs on oxidative stress, proinflammatory signaling and proliferative effects induced by RAS activation. AT1 R: angiotensin II type 1 receptor, eNOS: endothelial nitric oxide synthase, IL: interleukin, NADPH: reduced form of nicotinamide adenine dinucleotide phosphate, NF-kB: transcription factor nuclear factor-kB, NO: nitric oxide,, ROS: reactive oxygen species, TGF-b1: transforming growth factor b1, TNF-a: tumor necrosis factor-a. (Lines ending with a perpendicular segment represent inhibitory pathways).

Pulmonary hypertension

The clinical classification of pulmonary hypertension intends to categorize multiple clinical conditions into 5 groups according to their clinical presentation, pathological findings, haemodynamic characteristics and treatment strategy (45). COPD is classified in group 3 of pulmonary hypertension due to lung diseases and/or hypoxia (46). Proliferation of pulmonary artery smooth muscle cells and fibroblasts, endothelial dysfunction, hypoxia, loss of pulmonary vascular bed, hyperinflation especially during exercise, cigarette-smoke products, and pulmonary vascular inflammation (i.e., interleukin [IL]-6) or oxidative damage possibly through reduced neprilysin, implicate COPD in pulmonary hypertension (47). Activation of RAS, and especially Ang II, has been shown to promote cell proliferation, hypertrophy, migration and vasoconstriction and inflammation of the pulmonary vasculature, through stimulation of ROS, cytokines and other pro-thrombotic mediators (48).

Aldosterone seems to have similar actions in the pulmonary vascular network. Elevated levels of this hormone have been detected in experimental and human models with PH (49, 50). The evidence suggests that the vascular endothelium of the lungs is an extra-adrenal source of aldosterone production (48, 49). Aldosterone binds to mineralocorticoid receptors which are present in vascular cells, initiating signaling pathways that promote vascular remodeling seen in patients with PH (48, 49).

With respect to the correlation of ACE-2/Ang-(1-7) axis with PH, it has been found that ACE-2 and Ang-(1-7) levels are deficient in patients with PH and that strategies to increase these levels have been shown to lower pulmonary pressures and limit or reverse pulmonary vascular remodeling and fibrosis (51, 52).

Skeletal muscle dysfunction

Skeletal muscle dysfunction represents a systemic comorbidity in COPD (53). The weakness observed in COPD patients is most pronounced in locomotor muscles such us the quadriceps (54, 55). Reduced quadriceps strength in COPD is associated with exercise limitation (56), impaired health status (57), increased healthcare utilization(58) and mortality independent of airflow obstruction (59). Quadriceps weakness has also been shown to be a feature of early disease, and its development is likely to be multifactorial involving inflammation and oxidative stress (7). Ang II has potential relevance in the pathogenesis of muscle dysfunction in COPD, through modulation of this pathway (7). Evidence for an influence of RAS on muscle atrophy in COPD comes from experimental models, where infusion of Ang II causes cachexia via an inhibitory effect on the IGF-1 system and stimulation of the ubiquitin– proteasome proteolytic pathway (60).

The ACE-2/ Ang-(1-7) axis is also a pivotal regulator of skeletal muscle physiology (61, 62). ACE-2, the enzyme responsible for Ang-(1-7) production, is also found in skeletal muscle cells (63). Studies in murine models demonstrate that Ang-(1-7) diminishes the negative consequences induced by Ang II in skeletal muscle physiology (64–66).

ACE polymorphisms

Human ACE gene contains a functional polymorphism based on the presence [I (insertion)] or absence [D (deletion)] of a 287-base pair sequence on chromosome 17 (67). Therefore, three genotypes exist: II, ID and DD, and these have an approximate distribution of 25%, 50%, and 25%, respectively in a Caucasian population. ACE activity is highest in the subjects homozygous for the D allele (DD), is intermediate in the ID group and lowest in subjects homozygous for the I allele (II) (67). DD genotype has been associated with increased PAP (pulmonary arterial pressure) and PVR (pulmonary vascular resistance), when compared with the II genotype (68), and is more prevalent in smokers who develop COPD, being associated with a 2-fold increase in the risk for COPD (69). ACE polymorphism may also be related with low-grade systemic inflammation in COPD (70). This is evidenced by the fact that stable COPD patients have increased serum high-sensitivity CRP (C-reactive protein) across genotypes DD>ID>II, suggesting that RAS may contribute to the inflammatory response observed in COPD (70). Recent studies, however, have shown that ACE gene may not be a susceptibility gene for the origin of COPD. Mlak et al. suggested that  since the impact of I/D polymorphism of the ACE gene on COPD risk is moderate or negligible, ACE gene may be a disease-modifying gene and other molecular changes, that will help predict the development of this disease, should still be sought (71). A recent meta-analysis also reported that the I/D  polymorphism of the ACE gene may be associated with susceptibility to COPD in the Asian population but not in the Caucasian population, however these results need to be confirmed in a larger sample (72).

RAS blockers and COPD

All the above-mentioned data could be translated in COPD patients.^{Table 1} In effect, ACE is present at very high concentration in the lungs, and its activity is further increased by chronic hypoxia (73). Moreover, AT1 receptors are highly expressed within the lungs and they control alveolar epithelial cell apoptosis and lung fibroblast growth (74-77). As a result, Ang II appears to be a crucial mediator of lung injury and apoptosis (78). Lowering of ACE activity may have profound benefits in the long-term treatment of patients with COPD through (i) potential effects on pulmonary inflammation, architecture and vasculature, (ii) effects on respiratory drive and respiratory muscle function, (iii) effects on the efficiency of peripheral use of oxygen, and (iv) improvements in skeletal muscle functional capacity in the face of reduced oxygen delivery (79).

Increasing evidence supports a potentially beneficial impact of administration of RAS blockers in patients with COPD. Three large retrospective studies, have shown that ACE inhibitors and ARBs are associated with reduced exacerbations and mortality in COPD patients (80-82). Mancini et al. included 5853 patients divided in two cohorts: COPD patients having undergone myocardial revascularization (high CV risk cohort) and COPD patients without previous myocardial infarction (low CV risk cohort) (80). They reported that RAS blockers reduce both cardiovascular and pulmonary outcomes with the largest benefits occurring with the combination with statins (80). This combination reduces COPD hospitalizations and total mortality in both cohorts and myocardial infraction in the high-risk cohort (80). These beneficial effects were similar whether steroid users were included or not in the analyses (80). Mortensen et al. used Veterans Affairs administrative data and examined the association of prior outpatient use of statins and/or ACE inhibitors on mortality in 11.212 patients ≥65 years of age hospitalized with acute COPD exacerbations (81). The analysis showed that these drugs were associated with a significantly lower risk of death within 30 and 90 days from hospital admission, irrespective of the existence of comorbidities, and the same protective effects were found for concomitant use of these two drugs categories and in subsets with comorbid conditions, in which these drugs have demonstrated a therapeutic effect on mortality risk reduction (e.g., coronary heart disease and diabetes mellitus) (81). Intriguingly, in both studies, the largest benefits occurred with the combination of statins and either ACE inhibitors or AT1 receptor blockers. In a recent retrospective study including 4331 patients, ARBs were associated with lower mortality in COPD (82). Patients older than 40 years with COPD diagnosis were included and divided in two groups: an ARB-exposed group and a non-exposed group. The exposed group had higher median age (74.8 years old vs 69.2 years old) and more comorbidities (arterial hypertension, diabetes mellitus, congestive heart failure, chronic kidney disease, coronary heart disease, peripheral vasculopathy) (82). Although, the ARB-exposed cohort had higher emergency department utilization and hospitalization rates, mortality remained lower than in the nonexposed cohort (11.5% vs 29%) (82). In another study, Petersen et al. examined 1170 ever smokers with repeat spirometry tests over a minimum follow-up period of 3 years and reported that 32% of ever smokers exhibited rapid FEV₁ decline (83). Among ever smokers without a baseline spirometric abnormality, rapid decline was associated with an increased risk for incident COPD (83). The use of ACE inhibitors at baseline examination was protective against rapid decline, particularly among those with comorbid cardiovascular disease, hypertension or diabetes mellitus. This protective effect suggests a possible role for ACE inhibitors in attenuating lung function decline seen in smokers (83). Furthermore, a population-based cohort study of 4204 COPD patients, aged 40 years or older, in their first-ever exacerbation requiring hospitalization, showed that patients already receiving ARBs for a cardiovascular disease had lower in-hospital mortality (84). Di Marco et al. evaluated the effects of 4 weeks of treatment with enalapril on exercise performance in COPD patients (85). Enalapril did not influence the ventilatory response to exercise [Ve/Vco₂ (expired minute ventilation/carbon dioxide output) slope] or peak Vo₂. However, there was a significant improvement in oxygen pulse and peak work rate in the treatment group compared with placebo, suggesting an improvement in cardiopulmonary efficiency in COPD (85). Moreover, enalapril alongside a program of pulmonary rehabilitation in COPD patients without an established indication for ACE inhibition, reduced the peak work rate response to exercise training 86). Finally, an ongoing interventional, randomized study with 106 participants aims to determine whether losartan can stabilize or improve lung function in people who have COPD. The main outcomes of the study are the changes in percent emphysema on CT Scan and in FEV1 between baseline and month 12 (87). The studies that support a beneficial effect of RAS blockers in COPD are presented in Table 1.

Table 1. Main studies that support a beneficial effect of RAS blockers in COPD patients.

Author (year)	No. of pts	Type of study	Results/findings
Mancini et al. [77] (2006)	5853	Retrospective	Either ACEi or ARBs and statins reduced both cardiovascular and pulmonary outcomes, with the largest benefits occurring with the combination of these drugs. This combination was associated with a reduction in COPD hospitalization (RR 0.66, 95% CI 0.51 to 0.85) and total mortality (RR 0.42, 95% CI 0.33 to 0.52) not only in the high cardiovascular risk cohort but also in the low cardiovascular risk cohort (RR 0.77, 95% CI 0.67 to 0.87, and RR 0.36, 95% CI 0.28 to 0.45, respectively)
Mortensen et al. [78] (2009)	11 212	Retrospective	ACEi/ARB use (0.55, 95% CI 0.46-0.66) and statin use (OR 0.51, 95% CI 0.40-0.64) were significantly associated with decreased 90-day mortality in subjects hospitalized with a COPD exacerbation
Paulin et al. [79] (2017)	4331	Retrospective	ARBs use seems to be associated with a lower mortality in COPD. The survival in the ARBs exposed group was 76% (CI 95% 0,69-0,81) and 71% (CI 95% 69–73%) in the non exposed group. The unadjusted HR for mortality was 0.85 (CI 95% 0.67-1.07, p  =  0.17) and the adjusted HR by propensity score was 0.63 (CI 95% 0.50-0.80, p < 0.001)
Petersen et al. [80] (2014)	1170	Observational	Among ever smokers without a baseline spirometric abnormality, rapid decline was associated with an increased risk for incident COPD (OR 1.88; p = 0.003). The use of ACEi at baseline examination was protective against rapid decline, particularly among those with comorbid cardiovascular disease, hypertension, or diabetes (OR 0.48, 0.48, and 0.12, respectively; p ≤0.02 for all analyses)
Ho et al. [81] (2014)	4204	Population-based cohort	COPD patients hospitalized for first-ever COPD exacerbation receiving ARB for a cardiovascular disease, had lower in-hospital mortality (OR: 0.61; 95% CI: 0.38-0.98)
Di Marco et al. [82] (2010)	21	Double-blind, cross-over study	Enalapril did not affect the ventilatory response to exercise in COPD patients, but improved work rate and O2 pulse
Curtis et al. [83] (2016)	80	Double-blind, placebo-controlled, parallel-group randomized controlled trial	Enalapril, together with a program of pulmonary rehabilitation, in patients without an established indication for ACEi, reduced the peak work rate response to exercise training
Zeng et al. [85] (2013)	220	Retrospective	ACEi and ARBs reduce mortality in elderly male COPD patients
Kim et al. [86] (2016)	375	Case-control	ACEi/ARBs reduce the risk of pneumonia in COPD patients (OR = 0.51, 95% CI 0.27-0.98, p = 0.04)
Parikh et al. [87] (2017)	4472	Population-based	RAS blockers are associated with slowed progression of percent emphysema on chest CT (p  = 0.03)
Ekstrom et al. [88] (2013)	2249	Prospective	COPD patients receiving RAS blockers showed trends towards decreased mortality (HR, 0.90; 95% CI, 0.79-1.04; P = 0.166)
Kanazawa et al. [89] (2003)	36	Randomized double blind controlled trial	Captopril reduces mPAP in ID/II carriers
Bertoli et al. [90] (1986)	9		Captopril reduces mPAP(p < 0.05), mean pulmonary wedge pressure (p < 0.05) and total pulmonary resistance in COPD patients with pulmonary hypertension

COPD: chronic obstructive pulmonary disease; pts: patients; ACEi: angiotensin converting enzyme inhibitors; ARB: angiotensin receptor blocker; RR: risk ratio; CI: confidence interval; OR: odds ratio; HR: hazard ratio; CT :computed tomography; mPAP: mean pulmonary artery pressure.

In contrast to the above-mentioned data, a number of studies were unable to show benefit from the use of RAS blockers in patients with COPD. Ozyilmaz et al. included COPD patients and reported that ACE inhibitors/ARBs use paradoxically is an independent risk factor of frequent severe COPD exacerbations requiring hospital admission, however the study sample was relatively small (94). Observational data has also suggested that treatment with RAS blockers does not influence response to pulmonary rehabilitation (95). In addition, a randomised controlled trial by Shrikrishna et al. found that ACE-inhibition did not improve quadriceps function or exercise performance in COPD patients with quadriceps weakness (96). Several other studies with small sample sizes have also not shown positive effects of RAS inhibition in COPD (97–99).

Lastly, it is worth noting that that β-1 receptors cause renin release from the kidney and therefore, β-blockers seem to inhibit RAS system (100). Cardioselective β-blockers have proven safety in COPD (101, 102) and their use not only decreases the risk of overall mortality, but also reduces the risk of COPD exacerbation (103). However, studies are lacking and whether the beneficial role of β-blockers in COPD is attributed to renin inhibition remains to be seen.

Conclusions

COPD is an inflammatory disease with concomitant pulmonary fibrosis. RAS blockers have anti-inflammatory and antifibrotic properties. Recent retrospective studies have shown that ACE inhibitors and ARBs reduce mortality in COPD. In addition, there is evidence from small studies that ACE inhibitors improve pulmonary vascular resistance and peak work rate response to exercise training. However large randomized clinical trials are needed to confirm a positive effect of RAS blockers in COPD and in particular to establish the potential benefit on mortality in these patients.