A surprising connection between the lungs and the renin-angiotensin system is opening new doors for treating chronic obstructive pulmonary disease.
Published: June 2024 | Medical Research
For decades, the renin-angiotensin system (RAS) has been known primarily as a central regulator of blood pressure and fluid balance. Yet, recent scientific discoveries have revealed its surprising role in an unlikely area: chronic obstructive pulmonary disease (COPD).
This complex system, once thought to reside mainly in the cardiovascular system, is now understood to be active in our lungs, where it may play a crucial part in the inflammation and structural damage that characterizes COPD. This revelation is paving the way for innovative treatments that could potentially change how we manage this relentless respiratory condition 1 4 .
384M
Estimated global cases
40%
Of COPD patients may benefit
The renin-angiotensin system functions as a sophisticated chain reaction in the body. It begins with renin, an enzyme released by the kidneys, which cleaves angiotensinogen to form angiotensin I. This relatively inactive compound is then converted primarily in the lungs to angiotensin II by angiotensin-converting enzyme (ACE) embedded in lung capillaries 4 .
Did You Know? The lungs are particularly rich in ACE, making them a significant site for angiotensin II production.
Angiotensin II is the system's main effector molecule, traditionally known for constricting blood vessels and raising blood pressure. However, research has uncovered its darker side in COPD pathophysiology: it can stimulate pro-inflammatory mediators including interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), which contribute to the chronic inflammation that damages lung tissue in COPD patients 1 .
Beyond its effects on inflammation, angiotensin II also promotes activity of fibroblasts that increase collagen production, potentially playing a role in the pulmonary fibrosis observed in advanced COPD 1 4 .
The understanding that RAS contributes to COPD pathology naturally led to investigating whether RAS-inhibiting (RASi) medications could benefit patients. These drugs, including ACE inhibitors (ACEi) and angiotensin II receptor blockers (ARB), are commonly prescribed for hypertension and heart conditions.
A compelling Danish national observational study published in 2023 set out to determine if these drugs could reduce acute exacerbations and mortality in patients with severe COPD. The researchers employed an "active comparator" design, comparing COPD patients using RASi medications against those using bendroflumethiazide (another blood pressure medication) to minimize confounding factors 1 .
After following 38,862 patients with COPD for 12 months, the results were striking: the use of RASi treatment was associated with a consistently lower risk of acute exacerbations and death. The active comparator analysis showed a hazard ratio of 0.86, indicating a 14% reduction in risk compared to the alternative medication 1 .
These findings suggest that blocking the renin-angiotensin system may provide protective effects beyond cardiovascular health, potentially modulating the inflammatory processes that drive COPD progression.
Building on the foundation of RAS inhibitors, newer medications called angiotensin receptor-neprilysin inhibitors (ARNIs) show additional promise, particularly for patients who have both COPD and heart failure—a common combination in clinical practice 2 5 .
ARNIs work through a dual mechanism: they block angiotensin II receptors while simultaneously inhibiting neprilysin, an enzyme that breaks down beneficial natriuretic peptides. This dual action appears to offer advantages over traditional RAS inhibitors alone 2 .
ARNIs show particular promise for patients with both COPD and heart failure, a common comorbidity that complicates treatment and worsens prognosis.
A recent large retrospective cohort study compared ARNI versus RASi treatment in people with both COPD and heart failure. The results, published in 2025, revealed that ARNI users experienced significantly fewer respiratory complications:
| Outcome | ARNI Users | RASi Users | Improvement |
|---|---|---|---|
| COPD Exacerbations | 13.1% | 18.7% | 5.6% reduction |
| Acute Respiratory Failure | 16.2% | 22.0% | 5.8% reduction |
| Lower Respiratory Tract Infections | 16.9% | 22.9% | 6.0% reduction |
The hazard ratios consistently favored ARNI treatment across all respiratory outcomes, suggesting this newer class of medication may provide additional benefits for COPD patients with concurrent heart failure 2 5 .
The evolving understanding of RAS in COPD aligns with the broader shift toward precision medicine in respiratory diseases. The "treatable traits" approach recognizes that COPD is a heterogeneous condition with multiple underlying mechanisms that vary between individuals 3 .
Rather than a one-size-fits-all strategy, this paradigm seeks to identify specific, modifiable characteristics in each patient—whether pulmonary, extrapulmonary, or behavioral—and target them with tailored therapies 3 .
Airway inflammation, emphysema
Cardiovascular issues, muscle weakness
Smoking, physical inactivity
For some patients, RAS-related inflammation may represent a significant treatable trait that could be addressed with RASi or ARNI medications. Future research may help identify biomarkers that predict which COPD patients are most likely to benefit from these targeted approaches 3 .
RAS understood primarily as a cardiovascular system regulating blood pressure
Discovery of local RAS in various tissues including lungs
Research linking RAS to pulmonary inflammation and fibrosis
Observational studies showing benefits of RAS inhibitors in COPD
Randomized controlled trials and personalized medicine approaches
The discovery that the renin-angiotensin system plays a meaningful role in COPD has expanded our understanding of this complex disease. What was once considered primarily a cardiovascular pathway is now recognized as a contributor to pulmonary inflammation and tissue remodeling in COPD.
While current evidence supporting RASi and ARNI medications in COPD comes largely from observational studies, the findings are biologically plausible and consistent with our understanding of RAS in inflammatory processes. Randomized controlled trials are needed to confirm whether targeting the renin-angiotensin system can indeed modify COPD progression and outcomes 1 .
As research continues to unravel the intricate connections between cardiovascular and pulmonary health, patients and clinicians can anticipate more personalized, effective treatment strategies that address the multifaceted nature of COPD. The hidden link between the renin-angiotensin system and COPD exemplifies how looking beyond traditional organ-specific boundaries can reveal unexpected therapeutic opportunities.