# Regulation of type II cells in the repair of alveolar epithelial injury

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2024 · $641,027

## Abstract

ABSTRACT
The maintenance of an intact alveolar epithelial barrier is crucial for lung function. Failure of steady-state
replacement or post-injury regeneration of alveolar epithelial cells underlies the pathogenesis of many lung
diseases. In recent years, certain subgroups of cells have been identified as putative stem/progenitor cells in the
alveolar epithelium during homeostasis and regeneration. However, the identities of these cells and the
mechanisms regulating their behavior are still incompletely understood. Recent studies have indicated that some
immunity related signaling molecules can regulate the activity of alveolar epithelial progenitors, but the
mechanisms that direct these signaling events during lung homeostasis or regeneration have not been well
characterized. The objective of this proposal is to determine the distinct roles of immunity related signaling
pathways in the regulation of alveoli progenitor cell functions, both during steady-state maintenance as well as
post injury repair. An additional goal is to explore the possibility that dysregulation of these signaling processes
is related to chronical lung diseases such as emphysema or fibrosis. Two types of epithelial cells cover the lung
alveoli: alveolar type I cells (AT1) cover >95% of the surface area and facilitate O2-CO2 exchange, whereas
alveolar type II cells (AT2) are responsible for the secretion of surfactant. Importantly, AT2s also function as
stem/progenitor cells by undergoing self-renewal and differentiation into AT1s. In preliminary studies, we
demonstrated that 1) A small subset of AT2s (1-3% of total) showed stem cell characteristics indicating a role of
these cells for steady-state maintenance of alveoli. These cells had intrinsic NFκB and STAT1 activity and these
immunity related signals were able to regulate their progenitor functions; 2) After bacterial induced lung injury,
more AT2s are activated and behave as facultative stem cells to repair the alveoli. The reparative functions of
these cells are regulated by STAT1 and STAT3 mediated signals; and 3) AT2 specific disruption of STAT1
causes sustained fibrosis after bleomycin induced lung injury. This effect is likely induced by an aberrant
subpopulation of AT2/AT1 intermediate cells resulting from a failed transition of AT2s to AT1s. Based on these
data, we hypothesize that the progenitor function of a subset of AT2s in alveolar homeostasis and post injury
regeneration is regulated by distinct immunity related signals. Disruption of these signals is related to the
pathogenesis of chronic lung diseases. We will test these ideas with the following specific aims: Aim 1: To
determine how NFκB and STAT1 mediated immunity related signaling regulates the stem cell properties of
CD44high AT2 subsets during steady-state homeostasis. Aim 2: To determine the role of STAT1/STAT3
dependent, likely NFκB independent, immunity signaling in regulating the facultative progenitor cell functions of
AT2 cells in post injury ...

## Key facts

- **NIH application ID:** 10892272
- **Project number:** 5R01HL105947-10
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** YURU LIU
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $641,027
- **Award type:** 5
- **Project period:** 2012-05-01 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10892272

## Citation

> US National Institutes of Health, RePORTER application 10892272, Regulation of type II cells in the repair of alveolar epithelial injury (5R01HL105947-10). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10892272. Licensed CC0.

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