Conceptual approaches for treatment of phosgene inhalation-induced lung injury

Abstract

Toxic industrial chemicals are used throughout the world to produce everyday products such as household and commercial cleaners, disinfectants, pesticides, pharmaceuticals, plastics, paper, and fertilizers. These chemicals are produced, stored, and transported in large quantities, which poses a threat to the local civilian population in cases of accidental or intentional release. Several of these chemicals have no known medical countermeasures for their toxic effects. Phosgene is a highly toxic industrial chemical which was used as a chemical warfare agent in WWI. Exposure to phosgene causes latent, non-cardiogenic pulmonary edema which can result in respiratory failure and death. The mechanisms of phosgene-induced pulmonary injury are not fully identified, and currently there is no efficacious countermeasure. Here, we provide a proposed mechanism of phosgene-induced lung injury based on the literature and from studies conducted in our lab, as well as provide results from studies designed to evaluate survival efficacy of potential therapies following whole-body phosgene exposure in mice. Several therapies were able to significantly increase 24 hr survival following an LCt50–70 exposure to phosgene; however, no treatment was able to fully protect against phosgene-induced mortality. These studies provide evidence that mortality following phosgene toxicity can be mitigated by neuro- and calcium-regulators, antioxidants, phosphodiesterase and endothelin receptor antagonists, angiotensin converting enzymes, and transient receptor potential cation channel inhibitors. However, because the mechanism of phosgene toxicity is multifaceted, we conclude that a single therapeutic is unlikely to be sufficient to ameliorate the multitude of direct and secondary toxic effects caused by phosgene inhalation.

Phosgene Inhalation Causes Hemolysis and Acute Lung Injury

“…Phosgene may also be generated during welding and during fires involving plastics and solvents containing Cl 2 placing workers and first responders at serious risk (53). Phosgene exposure resulted in more than 80% of all chemical-related deaths in WWI (25) and it may have been used against civilian targets as recently as 2017 and 2018 in Syria http://www.worldinwar.eu/the-gas-used-in-khan-shaykhun-probably-the-phosgene-syria/.…”

Phosgene‐induced acute lung injury (ALI): differences from chlorine‐induced ALI and attempts to translate toxicology to clinical medicine

“…Canine, ovine, and porcine models have been used when studying the cardiopulmonary and hematological effects of methods used in humans. These models included protective ventilation in terminally anesthetized animals and pharmacological interventions such as steroids and bronchodilators [18–26]. Many of the drugs examined in these studies were shown to be ineffective in follow‐up proof‐of‐principle studies.…”

“…At much higher exposure intensities, this period may becomes markedly shorter [35,36]. Delayed mortality was also observed in experimental models of phosgene examined 80 years ago [24]; however, it was absent in more recent studies [37,38]. Accounting for the fact that the more recent industrial production of phosgene is by catalytic reaction of the high‐purity gases anhydrous chlorine and carbon monoxide, the presence of irritant impurities causing airway injury can be ruled out.…”

Pulmonotoxicyty of Synthetic Polymers Combustion Products

“…Спектр химических соединений, образующихся в результате горения твердых горючих материалов, не всегда определен, тем не менее можно выделить следующие группы токсичных веществ: общеядовитого (оксид углерода, цианиды, эпихлоргидрин) [2], пульмонотоксического (хлороводород, фосген, фтороводород) [11,20,35], цитотоксического (полихлорированные дибензо-n-оксины и дибензофураны) [24] и раздражающего (акролеин, формальдегид, ацетальдегид) [21,30] Помимо хлорсодержащих полимеров широкое применение в деятельности человека находят фторсодержащие материалы. Применение фторированных полимеров обусловлено их более высокой термостабильностью по сравнению с соот-ветствующими им углеводородными аналогами.…”

“…Экспериментально при отравлении фосгеном подтверждена низкая эффективность кортикостероидов [22,23], по-видимому, вследствие фармакодинамически более медленной реализации их эффектов на мишени воздействия фосгена. Признано, что терапевтическое воздействие при отравлении фосгеном имеет границы эффективности на уровне LCt 50-70 [20], что с учетом проведенного анализа данных о рисках воздействия определяет необходимость совершенствования средств медицинской защиты.…”