Angiotensin-(1-7) in asthma and pulmonary fibrosis: mechanisms of action, clinical safety, and nano-delivery strategies

Figures

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  FIGURE 1. Integrated signaling map of the renin–angiotensin system (RAS) and EGFR crosstalk in asthma and PF. The figure illustrates how Angiotensin II (Ang II), produced via ACE from angiotensin I, binds to AT1R and activates downstream pro-inflammatory and fibrotic pathways via JAK/STAT, PI3K/Akt/mTOR, TGF-β/SMAD2/3, and MAPK/ERK/NF-κB signaling. These cascades promote immune cell recruitment, cytokine release (TNF-α, IL-6, IL-1β, IL-4, IL-5), epithelial–mesenchymal transition (EMT), collagen deposition, and airway remodeling. EGFR acts as a central node amplifying fibrotic signaling. In contrast, Angiotensin-(1–7), generated from Ang II or Ang I via ACE2 (or alternatively via neprilysin (NEP), prolylendopeptidase (PREP), and prolylcarboxypeptidase (PRCP)) binds to the Mas receptor and activates protective pathways including PI3K/Akt/eNOS and SHP-1. These pathways inhibit fibroblast proliferation, suppress immune infiltration and cytokine release, enhance NO production, and preserve lung architecture. The figure highlights the balance between pathogenic Ang II–EGFR-driven responses and the protective Ang-(1–7)–Mas axis in lung inflammation and fibrosis.

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  FIGURE 2. Mechanisms of Antifibrotic Action of Angiotensin-(1–7) in PF. Ang-(1–7) exerts antifibrotic effects in PF through multiple mechanisms: inhibition of Hedgehog signaling (via GLI3 repressor dominance), restoration of autophagy and mitophagy to reduce oxidative stress and clear damaged proteins, and promotion of key homeostatic processes such as improved alveolar barrier integrity, enhanced vascular tone, and M2 macrophage polarization. Together, these pathways reduce fibroblast activation, collagen synthesis, inflammation, and fibrosis while preserving lung tissue integrity. Well-established mechanisms, including restoration of alveolar barrier integrity, vascular homeostasis, and immune modulation, are emphasized centrally in large text, whereas autophagy restoration and Hedgehog pathway modulation are emerging and/or model-specific mechanisms for which current evidence base remains comparatively limited are depicted as smaller sized text.

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  FIGURE 3. Nanotechnology-Based Formulations of Ang-(1–7) for Improved Drug Delivery. Nanocarrier strategies for Ang-(1-7) delivery include localized pulmonary approaches (intranasal liposomes, dry powder inhalers, PLGA nano/microparticles) and systemic methods (cyclodextrin inclusion complexes, plant bioencapsulation, dendrimers), whereby these formulations protect the peptide from enzymatic degradation, prolong circulation or lung residence, enable sustained and site-specific release, and reduce dosing frequency. To reflect the current state of evidence, cyclodextrin-based formulations represent the most extensively characterized delivery platforms, whereas pulmonary liposomes, dry powder inhalers, dendrimers, and plant-based bioencapsulation remain comparatively early-stage and are supported by more limited data. Collectively, they enhance Ang-(1-7) pharmacokinetics and therapeutic potential in asthma and PF.