# Strategies for Angiotensin Receptor Blocker Mediated Tissue Repair

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2020 · $622,479

## Abstract

Project Summary
COPD/emphysema, the fourth leading cause of death in the US, is a chronic inflammatory lung disorder
usually triggered by long-term cigarette smoke exposure. Although many therapies reduce the symptoms of
COPD, no interventions exist which arrest or reverse the extensive architectural and functional damage that
punctuate the disorder. Thus, therapies which not only reduce inflammation but also promote alveolar repair
(resident cell survival, regenerative matrix production) are ideally suited for COPD efficacy. Angiotensin
receptor blockers fulfill this dual role. The scientific premise is anchored on findings that: 1) angiotensin
receptor blockade reverses genetic emphysema and protects against cigarette smoke induced emphysema in
animal models manifest in reduced inflammation, reduced alveolar cell apoptosis and improved matrix
morphology and 2) supportive observational studies and a randomized double-blinded placebo controlled trial
of the angiotensin receptor blocker (ARB) Losartan (LOS) conducted under an NIH SCCOR mechanism that
showed reversal or stabilization of emphysema in a subset of treated patients with established disease over a
one year time frame. Such findings have led to an NIH-sponsored multicenter study of LOS in a cohort of
patients with established emphysema (LEEP Trial). These data importantly suggest an unanticipated alveolar
protective and reparative mechanism attached to angiotensin receptor blockade. Studies show that the
antagonism of TGFβ signaling induced by cigarette smoke (CS) or genetic perturbation is a direct ARB-
mediated protective mechanism in experimental emphysema. New preliminary data presented in current
proposal implicate enhanced PPARγ signaling by ARBs as a parallel and potentially reinforcing mechanism (to
TGFβ antagonism) for protection against CS-induced lung injury. LOS metabolites EXP3174 (3174) and
EXP3179 (3179) selectively activate AT1R-dependent and AT1R-independent cascades, respectively, in both
cell and animal model systems. Whereas AT1R-dependent repair engages selective antagonism of TGFβ
signaling, AT1R-independent repair promotes PPARγ agonism and antiinflammatory signaling. Aim 1 studies
delineate how LOS as a prototypical ARB attenuates CS-induced lung inflammation and injury and promotes
alveolar repair via coordinated activation of PPARγ plus inhibition of TGFβ. Aim 2 studies establish how ARBs,
via AT1R-dependent and -independent mechanisms, inhibit TGFβ cascades to modulate alveolar resident cell
survival and airspace repair in setting of CS-induced lung injury. Aim 3 studies utilize blood samples from
LEEP trial enrollees treated with LOS to 1) establish whether blood LOS and metabolite levels associate with
TGFβ and PPARγ pathway biomarkers and 2) identify CYP variants that associate with metabolite levels.
The proposed aims use primary cell models, experimental murine models and clinical samples from patients
with emphysema treated with LOS to clarify the strateg...

## Key facts

- **NIH application ID:** 10065083
- **Project number:** 1R01HL154343-01
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Enid R Neptune
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $622,479
- **Award type:** 1
- **Project period:** 2020-07-06 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10065083

## Citation

> US National Institutes of Health, RePORTER application 10065083, Strategies for Angiotensin Receptor Blocker Mediated Tissue Repair (1R01HL154343-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10065083. Licensed CC0.

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