Can ACE inhibitors help with pulmonary fibrosis?

Observational studies associate ACE inhibitor use with slower IPF progression and lower mortality. A 2025 analysis found that ACEi therapy initiated before IPF diagnosis was linked to reduced all-cause mortality. However, no randomized controlled trial has tested ACE inhibitors specifically for IPF. Current IPF guidelines do not include ACE inhibitors as standard therapy.

What is the ACE2 connection to lung fibrosis and COVID?

ACE2 converts pro-fibrotic angiotensin II into anti-fibrotic angiotensin(1-7). SARS-CoV-2 uses ACE2 as its cell entry receptor and downregulates it, potentially shifting the balance toward angiotensin II-driven fibrosis. This is one proposed mechanism for post-COVID pulmonary fibrosis in some patients. ACE2 expression is also reduced in IPF lungs independently of viral infection.

What peptides are being studied for lung fibrosis?

Several peptides target the angiotensin II/TGF-beta fibrotic pathway. GHK-Cu suppressed bleomycin-induced fibrosis in mice. Thymosin beta-4 fragment Ac-SDKP reduced fibroblast activation. Caveolin-1-derived peptide and M10 peptide both limited fibrosis in animal models. The AT2 receptor agonist C21 (buloxibutid) is the furthest along, currently in clinical trials for IPF.

Peptide Therapeutics for Pulmonary Fibrosis

Angiotensin II and Lung Scarring: Peptide-Driven Fibrosis

13 min read|March 21, 2026

Peptide Therapeutics for Pulmonary Fibrosis

3-5 years

Median survival after diagnosis of idiopathic pulmonary fibrosis, a condition where angiotensin II plays a central pro-fibrotic role.

Raghu et al., American Journal of Respiratory and Critical Care Medicine, 2022

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Idiopathic pulmonary fibrosis (IPF) replaces functional lung tissue with dense scar tissue, progressively suffocating patients over a median survival of 3 to 5 years after diagnosis. Angiotensin II, the eight-amino-acid peptide hormone best known for raising blood pressure, is now recognized as a central driver of this scarring process. It activates fibroblasts, stimulates collagen deposition, promotes epithelial cell death, and amplifies TGF-beta signaling through a self-reinforcing autocrine loop. For an overview of the full research pipeline targeting lung fibrosis with peptide therapeutics, see the pillar article on peptide therapeutics for pulmonary fibrosis.

Key Takeaways

Angiotensin II acts through the AT1 receptor on lung fibroblasts to induce TGF-beta1 secretion, collagen synthesis, and myofibroblast differentiation, creating a self-amplifying fibrotic loop
ACE2, the enzyme that converts angiotensin II into angiotensin(1-7), was first identified in 2000 as a counter-regulatory axis that opposes fibrosis^[1]
ACE inhibitor therapy was independently associated with reduced all-cause mortality in IPF patients in observational studies, while ARBs were not (Kreuter et al., CHEST, 2019)
GHK-Cu peptide inhibited bleomycin-induced pulmonary fibrosis in mice by suppressing TGF-beta1/Smad signaling^[2]
Thymosin beta-4 fragment Ac-SDKP reduced TGF-beta-induced fibroblast activation in human lung tissue^[3]
The AT2 receptor agonist C21 (buloxibutid) is in clinical trials for IPF, representing a peptide-system approach to anti-fibrotic therapy

The Renin-Angiotensin System in the Lung

The renin-angiotensin system (RAS) is typically discussed in the context of blood pressure regulation. Angiotensinogen, produced by the liver, is cleaved by renin to form angiotensin I, which ACE (angiotensin-converting enzyme) then converts into angiotensin II. In the vasculature, angiotensin II constricts blood vessels and raises blood pressure.

But the lung has its own local RAS. Lung epithelial cells, fibroblasts, and macrophages all express components of the angiotensin system. The lung is also the primary site where circulating ACE converts angiotensin I to angiotensin II, meaning the lung is exposed to high local concentrations of this peptide.

In 2000, Donoghue and colleagues discovered ACE2, a homolog of ACE that cleaves angiotensin II into angiotensin(1-7), a heptapeptide with opposing effects.^[1] This discovery revealed a counter-regulatory axis: where angiotensin II promotes fibrosis through the AT1 receptor, angiotensin(1-7) opposes fibrosis through the Mas receptor. The balance between these two peptides determines whether the lung repairs normally or scars pathologically.

How Angiotensin II Drives Lung Fibrosis

Fibroblast Activation and Myofibroblast Transformation

Angiotensin II binds the AT1 receptor on lung fibroblasts, triggering their transformation into myofibroblasts, the cells that produce excessive collagen and create scar tissue. Myofibroblasts express alpha-smooth muscle actin (alpha-SMA) and generate contractile forces that distort lung architecture. This transformation is mediated through MAPK, PI3K/Akt, and Rho/ROCK signaling pathways downstream of AT1 receptor activation.

TGF-beta1 Amplification Loop

Angiotensin II is a potent inducer of TGF-beta1 transcription and secretion. TGF-beta1 is considered the master pro-fibrotic cytokine, and its overexpression alone is sufficient to induce pulmonary fibrosis in animal models. The critical finding is that TGF-beta1 in turn upregulates angiotensinogen and ACE expression, creating a self-reinforcing autocrine loop: angiotensin II induces TGF-beta1, which induces more angiotensin II production. This positive feedback loop, documented in human IPF myofibroblasts and macrophages, explains why pulmonary fibrosis is progressive and self-perpetuating once established.

Epithelial Cell Apoptosis

Angiotensin II is pro-apoptotic for lung epithelial cells. In IPF, the alveolar epithelium is injured and fails to regenerate properly. Angiotensin II accelerates epithelial cell death through Fas ligand upregulation and mitochondrial apoptotic pathways. The loss of epithelial integrity removes the normal brake on fibroblast proliferation and allows aberrant wound healing to proceed.

Extracellular Matrix Remodeling

Beyond collagen synthesis, angiotensin II promotes the production of fibronectin, tissue inhibitors of metalloproteinases (TIMPs), and other matrix components while suppressing matrix metalloproteinases (MMPs) that would normally degrade excess matrix. The net effect is unopposed matrix accumulation, stiffening the lung parenchyma and impairing gas exchange.

The ACE2/Angiotensin(1-7)/Mas Axis: Built-In Protection

Angiotensin(1-7), produced by ACE2 cleavage of angiotensin II, opposes fibrosis at multiple levels:

Inhibits fibroblast proliferation and collagen synthesis
Reduces TGF-beta1 signaling
Protects epithelial cells from apoptosis (acting as an epithelial survival factor)
Promotes nitric oxide production and anti-inflammatory effects through the Mas receptor

In IPF lungs, ACE2 expression is reduced, shifting the balance toward the pro-fibrotic angiotensin II/AT1 receptor axis. This imbalance may be a fundamental driver of disease progression. Therapeutic strategies aimed at restoring the ACE2/angiotensin(1-7) axis represent a logical target.

ACE2 gained worldwide recognition during the COVID-19 pandemic as the cellular receptor for SARS-CoV-2. The virus downregulates ACE2 expression, potentially amplifying angiotensin II-driven fibrosis. Post-COVID pulmonary fibrosis has been documented in a subset of patients, and the angiotensin imbalance caused by viral ACE2 disruption is one proposed mechanism. Imaging studies have identified persistent fibrotic changes in approximately 10 to 20% of patients hospitalized with severe COVID-19, though the long-term progression and reversibility of these changes remain under active investigation. The COVID-19 pandemic accelerated research into the ACE2/angiotensin(1-7) axis for lung protection, with recombinant ACE2 and angiotensin(1-7) analogs both explored as potential therapies.

Clinical Evidence: ACE Inhibitors in IPF

Observational Data

A 2019 analysis by Kreuter and colleagues (CHEST, PMID 31047956) examined the association between angiotensin modulators and IPF outcomes. ACE inhibitor use was independently associated with slower disease progression, measured by forced vital capacity (FVC) decline. A 2025 study further found that ACE inhibitor therapy initiated in the 5 years before IPF diagnosis was associated with lower all-cause mortality.

ARBs (angiotensin receptor blockers), which block the AT1 receptor directly, were not associated with the same benefit. This paradox may reflect the fact that ACE inhibitors reduce angiotensin II production (preserving the angiotensin(1-7) axis), while ARBs block AT1 signaling but allow angiotensin II to accumulate and potentially act through alternative pathways.

AT2 Receptor Agonism: Buloxibutid (C21)

The AT2 receptor, unlike AT1, mediates anti-inflammatory and anti-fibrotic effects. A 2026 review examined the potential of AT2 receptor agonists for IPF treatment, with the compound C21 (buloxibutid) advancing to clinical trials. This represents a strategy of activating the protective arm of the angiotensin system rather than simply blocking the harmful arm.

Caveats

All clinical evidence linking angiotensin modulation to IPF outcomes comes from observational studies and retrospective analyses. No randomized controlled trial has been completed specifically testing ACE inhibitors or ARBs as IPF therapy. Confounding by indication (patients with hypertension receiving ACE inhibitors may differ from those who do not) limits causal inference. The ongoing clinical trials with C21 will provide the first prospective data.

Other Peptides That Counter Angiotensin II-Driven Fibrosis

GHK-Cu

The copper tripeptide GHK-Cu, known primarily for skin regeneration, inhibited bleomycin-induced pulmonary fibrosis in mice by suppressing TGF-beta1/Smad signaling and reducing collagen deposition.^[2] GHK-Cu also downregulated inflammatory cytokines and oxidative stress markers in lung tissue. This positions GHK-Cu as a peptide that intersects with the angiotensin II/TGF-beta axis at the TGF-beta signaling level.

Thymosin Beta-4 and Ac-SDKP

Thymosin beta-4 and its N-terminal fragment Ac-SDKP reduced TGF-beta-induced fibroblast-to-myofibroblast transition in human lung fibroblasts.^[3] Ac-SDKP is naturally produced by the hydrolysis of thymosin beta-4 and is degraded by ACE. ACE inhibitors increase circulating Ac-SDKP levels, which may contribute to their anti-fibrotic benefit in IPF beyond simple angiotensin II reduction.

Caveolin-1-Derived Peptide (CSP)

A peptide derived from caveolin-1 limited the development of pulmonary fibrosis in preclinical models by modulating fibroblast biology and reducing excessive matrix production.^[4]

M10 Peptide

The M10 peptide attenuated silica-induced pulmonary fibrosis in mice by inhibiting Smad2 phosphorylation, a key downstream mediator of TGF-beta signaling.^[5] This parallels the anti-fibrotic approach of targeting TGF-beta signaling downstream of angiotensin II.

Pulmonary fibrosis frequently leads to pulmonary hypertension as scar tissue compresses and destroys lung blood vessels. The angiotensin system contributes to both conditions. A 2019 study tested the combination of an angiotensin II receptor blocker with sacubitril (a neprilysin inhibitor that prevents degradation of protective natriuretic peptides) for pulmonary hypertension. The combination approach of simultaneously blocking the harmful angiotensin II pathway while preserving beneficial natriuretic peptides represents the dual-axis therapeutic strategy that is increasingly applied to fibrotic lung disease.^[6]

The defensins expressed in lung epithelium are another peptide system affected by fibrosis. As the epithelial barrier is destroyed by angiotensin II-driven apoptosis, defensin production declines, increasing vulnerability to respiratory infections. IPF patients have elevated rates of bacterial pneumonia, and the loss of antimicrobial peptide defense is one contributing factor. This creates a vicious cycle: fibrosis impairs innate immunity, infection triggers further inflammation, and inflammation accelerates fibrosis.

The Bigger Picture: Angiotensin II as a Systemic Fibrosis Driver

Angiotensin II drives fibrosis not only in the lung but in the heart, kidney, liver, and skin. The same TGF-beta amplification loop operates across organs. Collagen peptide biomarkers in liver fibrosis reflect the same excessive matrix deposition that occurs in pulmonary fibrosis. Cardiac fibrosis after myocardial infarction involves angiotensin II-driven myofibroblast activation. The RAS is a systemic fibrosis system, and the lung is one of its most vulnerable targets.

This systemic perspective explains why ACE inhibitors and ARBs, originally developed for hypertension, have shown organ-protective effects across multiple fibrotic conditions. It also explains why food-derived ACE-inhibitory peptides have attracted interest beyond blood pressure management.

Limitations and What Is Missing

The mechanistic understanding of angiotensin II in pulmonary fibrosis is robust, supported by extensive cell culture, animal model, and human tissue data. The clinical translation is where evidence thins. No prospective RCT has tested ACE inhibitors specifically for IPF, and the observational data, while consistent, cannot establish causation. The ongoing C21 trials will be the first controlled test of the angiotensin hypothesis in IPF.

Animal models of pulmonary fibrosis (bleomycin, silica) do not perfectly recapitulate human IPF. Bleomycin fibrosis resolves spontaneously in mice, while human IPF is progressive. This fundamental difference means that drugs effective in mice may not translate to human benefit.

The approved IPF therapies, pirfenidone and nintedanib, slow disease progression but do not reverse established fibrosis. Whether angiotensin modulation could complement these agents, potentially through inhaled peptide delivery, remains untested.

The heterogeneity of IPF adds complexity. Some patients progress rapidly while others remain stable for years. Whether the angiotensin II/TGF-beta loop is equally active across all IPF subtypes is unknown. Biomarkers that identify patients with high local angiotensin II activity could help select patients most likely to benefit from RAS-targeted therapy, but no validated biomarker for this purpose currently exists.

Drug-drug interactions also require consideration. Many IPF patients take antihypertensive medications, and some are already on ACE inhibitors or ARBs for cardiovascular indications. Whether intentional RAS modulation for anti-fibrotic purposes requires different dosing, timing, or agent selection than blood pressure management has not been systematically studied. The lung-specific effects of systemically administered RAS modulators depend on drug distribution, local enzyme activity, and tissue-specific receptor expression that are incompletely characterized.

The Bottom Line

Angiotensin II contributes to pulmonary fibrosis through a self-reinforcing loop with TGF-beta1 that drives fibroblast activation, epithelial cell death, and excessive matrix deposition. The counter-regulatory ACE2/angiotensin(1-7) axis is suppressed in IPF lungs. Observational data associate ACE inhibitor use with better IPF outcomes, and the AT2 receptor agonist C21 is in clinical trials. Several peptides, including GHK-Cu, thymosin beta-4, and caveolin-1-derived peptides, target downstream components of this fibrotic cascade. Prospective clinical trials are needed to move from mechanistic understanding to proven therapy.

Frequently Asked Questions

Angiotensin II is a significant driver of pulmonary fibrosis, though not the sole cause. It activates lung fibroblasts through the AT1 receptor, induces TGF-beta1 secretion, promotes epithelial cell death, and stimulates collagen production. A self-reinforcing angiotensin II/TGF-beta1 loop has been documented in human IPF tissue. Angiotensin II acts alongside other pro-fibrotic mediators in a complex process.

ACE inhibitors reduce angiotensin II production, which preserves the protective ACE2/angiotensin(1-7) pathway. They also increase levels of Ac-SDKP, an anti-fibrotic peptide normally degraded by ACE. ARBs block the AT1 receptor but allow angiotensin II to accumulate, which may activate alternative pathways. The observational data showing benefit for ACEi but not ARBs in IPF is consistent with this mechanistic distinction.

Established pulmonary fibrosis with dense scarring is not currently reversible with any approved therapy. Pirfenidone and nintedanib slow progression but do not reverse existing scar tissue. Research into anti-fibrotic peptides and angiotensin modulation aims to halt progression and, in early disease, potentially prevent scar formation. True reversal of established fibrosis remains a major unmet therapeutic challenge.