A brief history of carbon monoxide and its therapeutic origins

Carbon monoxide (CO) is probably best known as a poisonous gas arising from incomplete combustion of coal [4]. However, CO is also an endogenously produced neurotransmitter referred to as a gasotransmitter along with nitric oxide (NO) and hydrogen sulfide (H₂S). The premier source of endogenous CO is the enzymatic catabolism of heme by heme oxygenase (HMOX, commonly abbreviated as HO in literature) though there are numerous enzymes and minor sources [5]. The chemistry of HMOX is partially observable to the unaided eye as exemplified by the healing of a contusion as the dark red/black hue of heme undergoes HMOX biotransformation to biliverdin (blue/green) followed by reduction via biliverdin reductase to the final yellow pigment of bilirubin (commonly associated with jaundice) [6]. There are two common isoforms HMOX. HMOX1 (heat shock protein HSP32) is the stress-induced 32 kDa isoform triggered by as variety of xenobiotics, signaling cascades, and stressors such as hypoxia and oxidative stress [7]. HMOX2 is a 36 kDa homologue constitutively expressed in the brain, testes, and throughout the gastrointestinal tract; although widely regarded as non-inducible, adrenal glucocorticoids have been identified as HMOX2 inducers [8,9]. The human microbiome likewise contains a multitude of HMOX-like enzymes [10]. CO primarily undergoes pulmonary excretion, though it is possible for passive diffusion through skin epithelium or oxidation to carbon dioxide (CO₂) by cytochromes and microbiota [10]. CO has an approximate 240-fold greater affinity for hemoglobin than oxygen, hence most endogenous CO is stored as carbonylhemoglobin (COHb) [11]. The typical non-smoker has systemic levels of under 2% COHb [12].

CO is recognized to have cytoprotective roles and therapeutic potential for many indications to include, but not limited to: anti-inflammatory, anti-malarial, anti-cancer, and anti-microbial with protective roles against ischemia-reperfusion injury and improving organ transplantation prognosis [13]. Therapeutic benefits of exogenously applied CO have been observed in preclinical models at levels as low as 10 ppm [14]. The physiological and pharmaceutical significance of the CO/HMOX system has been extensively studied over the past twenty years (the reader is directed to the following literature [[15], [16], [17], [18], [19], [20], [429]]).

As the CO/HMOX field has matured through collective global efforts, the aim of this work is to review the origins and trace evidence within archaic literature as they may point toward the therapeutic potential of CO. As such, the body of this text focuses on historical events predating the modern era of research (e.g. anecdotal evidence, stories, letters, etc.) that generally do not meet the rigor of modern scientific literature. In fact, this paper interfaces with non-scientific disciplines in efforts to bridge this field with its fons et origo. This is not a complete historical account of CO; the scope of this work is aimed at therapeutic and physiological origins and with historical milestones and toxicology presented in brief (see Fig. 1). In this historically themed review, individual recognition for contributions over the past several decades are not discussed. The reader is redirected to reviews extensively cover the modern era of research progress e.g. Refs. [15,[21], [22], [23], [24], [25], [26]] and a recent review highlighting historical milestones of the modern era [27]. As search engines continue to improve and more archaic literature becomes digitally accessible (e.g. accurately translated), it is certain future researchers will identify additional physiological and therapeutically relevant events not covered in this review.

Historical background and physiological origins

It is estimated that 10% of carbon throughout the cosmos is stored as carbon monoxide (CO) [1]. Earth's prebiotic atmosphere included the trinity of gasotransmitters CO, NO, and H₂S which all biological organisms have co-evolved with [2]. The earliest analytical evidence for a presence of atmospheric CO was detected in ice cap samples (500 BCE) [28]. The history of CO can be loosely traced to prehistoric origins with rudimentary knowledge emerging in the late middle ages. This section presents

Therapeutic origins

Trace evidence for therapeutic application of CO appeared in the late 1700s. Synthetic therapeutic gases emerged when Thomas Beddoes wrote to Erasmus Darwin (grandfather of Charles Darwin) suggesting medicinal application of factitious airs which were later studied at the Pneumatic Institute (1793) [85,236,237]. Among the many gases Beddoes experimented with, the most applicable to CO are those arising either from chalk or the combination of water and hot coals (water gas) which he referred to

Conclusion

There is no doubt mankind has maintained a complex relationship with CO since the stone age. Despite CO bedeviling dwellings over the past millennia, the forefathers of chemistry and medicine provided a broad foundation and correctly suggested a therapeutic potential for this molecule. Although the origin on the therapeutic potential of CO was not supported by a molecular mechanism by virtue of emerging in the 1790s, the courage to purpose a beneficial role for CO despite its ghastly reputation

Funding

This research was funded by The German Research Foundation (Deutsche Forschungsgemeinschaft - DFG) grant numbers: DFG #374031971 CRC/TR 240, Projekt B03 (CPH), DFG WO 2209/2-1 and GO 2158/6-1 (UG).

Declaration of competing interest

None.

Acknowledgments

The framework for this review was a chronological compilation of the collective efforts of carbon monoxide reviews and chapters over the past century, the content of which has been made accessible by recent advances in digital technology. Special thanks are extended to Dr. Lenka Tomasova, Prof. Dr. Oliver Grundmann, and Ms. Amelia & Chloe Hopper for their insights.