Context

Methyl mercaptan (CH₃SH) is a colorless, toxic gas with potential for occupational exposure and used as a weapon of mass destruction. Inhalation at high concentrations can result in dyspnea, hypoventilation, seizures, and death. No specific methyl mercaptan antidote exists, highlighting a critical need for such an agent. Here, we investigated the mechanism of CH₃SH toxicity, and rescue from CH₃SH poisoning by the vitamin B₁₂ analog cobinamide, in mammalian cells. We also developed lethal CH₃SH inhalation models in mice and rabbits, and tested the efficacy of intramuscular injection of cobinamide as a CH₃SH antidote.

Results

We found that cobinamide binds to CH₃SH (K_d = 84 µM), and improved growth of cells exposed to CH₃SH. CH₃SH reduced cellular oxygen consumption and intracellular ATP content and activated the stress protein c-Jun N-terminal kinase (JNK); cobinamide reversed these changes. A single intramuscular injection of cobinamide (20 mg/kg) rescued 6 of 6 mice exposed to a lethal dose of CH₃SH gas, while all six saline-treated mice died (p = 0.0013). In rabbits exposed to CH₃SH gas, 11 of 12 animals (92%) treated with two intramuscular injections of cobinamide (50 mg/kg each) survived, while only 2 of 12 animals (17%) treated with saline survived (p = 0.001).

Conclusion

We conclude that cobinamide could potentially serve as a CH₃SH antidote.

Chlorine exposure can cause severe airway injuries. While the acute effects of chlorine inhalation are well-documented, the structural changes resulting from the post-acute, high-level chlorine exposure remain less understood. Airway sloughing is one of the standards for doctors to evaluate the lung function. Here, we report the application of a high-resolution swept-source optical coherence tomography system to investigate the progression of injury based on airway sloughing evaluation in a chlorine inhalation rabbit model. This system employs a 1.2 mm diameter flexible fiberoptic endoscopic probe via an endotracheal tube to capture in vivo large airway anatomical changes before and as early as 30 min after acute chlorine exposure. We conducted an animal study using New Zealand white rabbits exposed to acute chlorine gas (800 ppm, 6 min) during ventilation and monitored them using optical coherence tomography (OCT) for 6 h. To measure the volume of airway sloughing induced by chlorine gas, we utilized deep learning for the segmentation task on OCT images. The results showed that the volume of chlorine induced epithelial sloughing on rabbit tracheal walls initially increased, peaked around 30 min, and then decreased. Furthermore, we utilized a spectral encoded interferometric microscopy system to study ex vivo airway cilia beating dynamics based on Doppler shift, aiding in elucidating how chlorine gas affects cilia beating function. Cilia movability and beating frequency were decreased because of the epithelium damage. This quantitative approach has the potential to enhance the diagnosis and monitoring of injuries from toxic gas inhalation and to evaluate the efficacy of antidote treatments for these injuries.