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Therapeutic potential for NPS-2143 as treatment for chlorine induced lung edema

Award Number: R21ES037285
ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/02/2026
PERIOD OF PERFORMANCE END DATE: 07/01/2028

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Therapeutic potential for NPS-2143 as treatment for chlorine induced lung edema - Abstract: One hallmark of lung injury caused by chlorine (Cl2) inhalation is the inhibition of lung epithelial ion and water transport, leading to fluid accumulation within alveolar spaces and subsequent edema formation. Alveolar edema, a severe clinical condition resulting from Cl2 exposure, currently lacks effective treatment options aimed at directly increasing the rate of fluid reabsorption from the affected alveolar spaces. The lung's alveolar epithelium serves as a critical barrier between inhaled air and the interstitium/blood, facilitating the exchange of oxygen (O2) and carbon dioxide (CO2) between these compartments. The lung's inner surface is lined with a thin liquid layer (~0.2 μm), known as the epithelial lining fluid (ELF). The consistency of the ELF depth around ~0.2 μm indicates the involvement of precise homeostatic regulation by lung epithelial cells. Dysfunction of alveolar epithelial function can result in alveolar flooding and lung edema development, particularly upon Cl2 inhalation. The hydration of Cl2 within the ELF generates hypochlorous acid (HOCl) and hydrochloric acid (HCl), both of which are corrosive substances that interact with cellular components, damaging plasma membrane lipids, proteins, and extracellular matrix components. Exposure of mice to Cl2 (400 ppm for 30 minutes) led to an increase in the lung wet/dry (W/D) ratio, reduced alveolar fluid clearance (AFC), and impaired the epithelial sodium channel (ENaC) function in alveolar epithelial cells (AECs) type 1 and type 2. Notably, inhibition of the calcium-sensing receptor (CaSR) using 1 µM of the calcilytic NPS2143, administered 1 hour post Cl2 exposure, prevented and/or reversed these chlorine-induced pulmonary alterations. These findings underscore the therapeutic potential of NPS2143 in restoring alveolar ion and water transport vital for resolving lung edema caused by Cl2 inhalation. Based on these compelling data, we hypothesize that Cl2 inhalation instigates lung edema by activating CaSR, prompting intracellular signaling pathways that inhibit alveolar sodium transport. Analysis demonstrated that NPS2143 (1 µM), administered one hour following Cl2 exposure, normalized lung W/D ratio, AFC, and ENaC activity to control levels. Understanding the molecular mechanisms by which Cl2 disrupts alveolar sodium and water transport is essential for crafting innovative therapeutic strategies to restore lung physiological functions. We aim to test NPS2143's therapeutic capacity in reinstating alveolar epithelial function following Cl2 inhalation, informed by these insights.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $409,750 )
2026	2026	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Environmental Health	000	1	7/3/2026	NEW	$409,750
														Subtotal = $409,750

Grand Total All Awards = $409,750

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Therapeutic potential for NPS-2143 as treatment for chlorine induced lung edema

Award Number: R21ES037285

ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/02/2026

PERIOD OF PERFORMANCE END DATE: 07/01/2028

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