# Airway stem cell activation in the mitigation of halogen-induced lung injury

> **NIH NIH R21** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2020 · $222,750

## Abstract

Halogens are very reactive and pose significant threat to public health when released
into the atmosphere in large quantities during transportation and industrial accidents, as well as
acts of terrorism. While exposure to high doses of Cl2 causes mortality, surviving victims develop
serious respiratory disorders. Airway dysfunction due to impaired repair is a major cause of
increased morbidity and mortality. Basal cells (BC) are the primary stem/reparative cells of the
airway epithelium. Our studies demonstrate that high tissue factor (TF)-expressing BC
populations exhibit enhanced proliferative and clone-forming capacity and that BCs can replenish
and restore injured airway epithelium. Further, we show that TF knockdown reduced repair of
mechanically injured BC monolayer. We also demonstrate that low-TF expressing mice have
increased airway injury due to loss of BCs. Other studies have shown that the airways of low-TF
expressing mice are fragile and that active recombinant tissue factor (rTF) adminstration restored
the LPS-injured airways. Sequential bronchial biopsies of a victim of acute Cl2-inhalation revealed
BC mediated repair of the injured epithelium. However, BC dysfunction can lead to abnormal
repair and bronchiolitis obliterans (BO) like pathology in the lungs of mice exposed to Cl2. In our
mice model of Cl2 exposure we have observed extensive release of BCs in the BALF. Additionally,
in these mice TF expression was decreased in BCs. In our preliminary studies rTF
supplementation after Cl2 exposure prevented BC sloughing in the airways of mice. Additionally,
we also demonstrate that basal cell function can be restored through increased TF. Thus, we
established a direct correlation between TF activity and BC function in our model of Cl2-inhalation.
The role of exogenous TF in restoring BC progenitor function in the context of halogen induced
airway injury is novel. Therefore, we hypothesize that loss of basal cells following exposure to
halogens impairs airway repair leading to increased morbidity and mortality and that
restoring basal cell function through TF can mitigate injury. This hypothesis will be tested
through the following specific aims: Aim 1. Determine the effect of halogens on airway epithelial
basal cell function; Aim 2. Determine the effects of depleting airway epithelial basal cell function
on halogen toxicity; Aim 3. Determine the effects of restoring basal cell function on halogen
toxicity. Rescue therapies and treatment strategies are non-existent for survivors of high dose Cl2
exposures. BC TF restoration to seal hemorrhaging airways and enhance repair efficiency
represents improved opportunities for treating halogen-induced pulmonary toxicity and mitigating
subsequent onset of RADS that are so far lacking.

## Key facts

- **NIH application ID:** 9935814
- **Project number:** 1R21ES030525-01A1
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Shama Ahmad
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $222,750
- **Award type:** 1
- **Project period:** 2020-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9935814

## Citation

> US National Institutes of Health, RePORTER application 9935814, Airway stem cell activation in the mitigation of halogen-induced lung injury (1R21ES030525-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9935814. Licensed CC0.

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