# Structural Plasticity in Compensatory Lung Growth and Remodeling

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2020 · $690,207

## Abstract

Project Summary
Following loss of ~58% of lung units by right pneumonectomy (PNX) in adult canines, supra-threshold tissue
and microvascular mechanical stress additively stimulate compensatory lung growth and remodeling (CLGR)
of remaining lung units, leading to regeneration of alveolar tissue-capillaries and restoring ~50% of the lost
function. This robust model of regeneration mimics the consequences of destructive lung disease, allowing
exploration of adaptive mechanisms in the remaining functioning lung units capable of responding, irrespective
of the specific pathology causing destruction. CLGR is plastic; supplementation of growth promoters, e.g.,
retinoic acid or erythropoietin (Epo), further enhances alveolar tissue-capillary formation in remaining lobes but
has not further augmented lung function, indicating a structure-function discrepancy in response to exogenous
stimulation. This may be because mechanically induced lung growth also increases oxidative stress, which in
turn limits growth and remodeling; also newly added tissue-capillaries may distort architecture of the acinus,
the fundamental unit of gas exchange, and detract from functional enhancement.
Anti-oxidation may be a key factor in resolving the structure-function discrepancy. Oxidative stress, paracrine
Epo signaling via its receptor (EpoR), and the circulating anti-oxidative factor αKlotho, are all persistently
elevated during post-PNX CLGR. αKlotho acts upstream of EpoR to enhance EpoR cytoprotection in vitro,
suggesting that αKlotho may also enhance angiogenic stimulation via the Epo-EpoR axis. We propose that
optimal CLGR requires a balance between mechanical signals and cytoprotection, and concurrent αKlotho
anti-oxidation may enhance EpoR-stimulated angiogenesis in CLGR.
Aim 1 will test the hypothesis that αKlotho and EpoR mutually enhance each other to relieve oxidative stress
in the lung, using mice with lung-specific conditional EpoR deletion ± genetic Klotho insufficiency, exposed to
oxidant challenge. Aim 2 will test the hypothesis that αKlotho augments EpoR-mediated angiogenic
stimulation and acinar remodeling in CLGR to facilitate translation of structural growth into functional gain. We
will concurrently deliver nanoparticles containing EpoR and/or αKlotho cDNA to post-PNX young and adult
canine lungs, to assess alveolar-capillary regrowth (in vivo CT and electron microscopy), angiogenic factor and
progenitor cell distribution, stratified acinar architecture (microCT) and functional compensation. Finally, we will
develop and compare (αKlotho+EpoR) cDNA treatment in PNX model with a canine unilateral elastase
emphysema model characterized by reduced mechanical stress and elevated inflammatory oxidative stress.
These issues of stratified acinar remodeling, growth-stimulation vs. cytoprotection balance, and overcoming
structure-function discrepancy in CLGR, have not been examined; they directly impact any intervention aimed
at promoting repair and regeneration of...

## Key facts

- **NIH application ID:** 9837462
- **Project number:** 5R01HL134373-04
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Connie C. W. Hsia
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $690,207
- **Award type:** 5
- **Project period:** 2017-01-01 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9837462

## Citation

> US National Institutes of Health, RePORTER application 9837462, Structural Plasticity in Compensatory Lung Growth and Remodeling (5R01HL134373-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9837462. Licensed CC0.

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