NIH grant: Therapeutic potential for NPS-2143 as treatment for chlorine induced lung edema (1R21ES037285-01A1)

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NIH grant 1R21ES037285-01A1: Therapeutic potential for NPS-2143 as treatment for chlorine induced lung edema
Institute: {'code': 'ES', 'abbreviation': 'NIEHS', 'name': 'National Institute of Environmental Health Sciences', 'admin_org_id': '12500022', 'admin_funding_url': ''}. PI: Ahmed  Lazrak. Award: $409750.
Start: 2026-07-02T00:00:00.
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.

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