# Epithelial Progenitor Cell Dysfunction in the Fibroproliferative Process of CLAD

> **NIH NIH P01** · CEDARS-SINAI MEDICAL CENTER · 2020 · $468,000

## Abstract

Project Summary/Abstract
Lung transplant (LT) is an option for advanced lung diseases; unfortunately, due to post-transplant complications,
both infections and non-infections (i.e., rejections), which leads to chronic lung allograft dysfunction (CLAD) it is
only a treatment and not a cure. The hallmark of CLAD is the displacement of normal epithelium by a relentless
deposition of extracellular matrix. Currently, there are no effective therapies for the prevention or treatment of
CLAD. This proposal will use both a novel mouse orthotopic-transplant-with-regrafting to model the pathobiology
of CLAD and human translational studies to evaluate mechanisms that lead to epithelial progenitor cell (EPC)
loss and fibrogenesis during CLAD. We have previously shown that a type 1/17 inflammatory environment
promotes acute rejection (AR), while the type 2 fibroproliferative environment supports the development of
fibrosis in CLAD. Our preliminary data suggests that loss of epithelial progenitor cell reserves (EPCR) leads to
fibroplasia and CLAD. Additionally, we propose that IL-22, in part through a p53-dependent pathway, functions
differently at different stages post-transplantation. During the early stages of allograft injury, IL-22 is beneficial
by promoting EPCR expansion. However, later on, IL-22 influences fibroblasts thereby stimulating the
development of fibrosis in CLAD. The consequence of IL-22 upon the lung allograft depends on the cell type on
which its receptor is expressed. During the inflammatory type 1/17 phase, the EPCR expresses the heterodimeric
IL-22 receptor (IL-22R1 and IL-10R2), while fibroblasts do not. Thus, during early injury stages post-LT, IL-22
mediates downregulation of p53 signaling just in epithelial cells, thereby allowing progenitor cells to proliferate
and regenerate the lung epithelium. Conversely, when continued insults to the lung allograft leads to a
fibroproliferative type 2 environment, the IL-22 receptor expression is induced on fibroblasts and reduced on
EPCR. Thus, at this later stage, IL-22 interacts preferentially with its receptor on fibroblasts, skewing them
towards an invasive, fibrotic phenotype resulting in CLAD. Our preliminary pre-clinical data in murine models
suggest that manipulating IL-22 and p53 can affect the outcome of CLAD, either protective via promotion of EPC
regeneration or harmful via promotion of fibroplasia. Moreover, we will insure the relevance of these pathways
in humans using lung transplant (LT) recipients biological samples that include BALF protein and cultured
fibroblasts as well as brushing of the allograft airway epithelial cells.

## Key facts

- **NIH application ID:** 9957131
- **Project number:** 5P01HL108793-08
- **Recipient organization:** CEDARS-SINAI MEDICAL CENTER
- **Principal Investigator:** JOHN A BELPERIO
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $468,000
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9957131

## Citation

> US National Institutes of Health, RePORTER application 9957131, Epithelial Progenitor Cell Dysfunction in the Fibroproliferative Process of CLAD (5P01HL108793-08). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9957131. Licensed CC0.

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