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.

Public Health Relevance

Halogens are very reactive and pose significant threat to public health when released into the atmosphere in large quantities. Airways and lungs are the primary site of injury however, aberrant repair often leads to respiratory morbidities such as reactive airway dysfunction syndrome, RADS, in survivors. This work will identify novel endogenous BC/stem cell stimulation based strategies to repair injured airway epithelium and treat diseases such as RADS in Cl2 exposed victims.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1)
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Nadadur, Srikanth
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University of Alabama Birmingham
Schools of Medicine
United States
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