A brief history of carbon monoxide and its therapeutic origins.

It is estimated that 10% of carbon throughout the cosmos is in the form of carbon monoxide (CO). Earth's earliest prebiotic atmosphere included the trinity of gasotransmitters CO, nitric oxide (NO), and hydrogen sulfide (H2S), for which all of life has co-evolved with. The history of CO can be loosely traced to mythological and prehistoric origins with rudimentary understanding emerging in the middle ages. Ancient literature is focused on CO's deadly toxicity which is understandable in the context of our primitive relationship with coal and fire. Scientific inquiry into CO appears to have emerged throughout the 1700s followed by chemical and toxicological profiling throughout the 1800s. Despite CO's ghastly reputation, several of the 18th and 19th century scientists suggested a therapeutic application of CO. Since 2000, the fundamental understanding of CO as a deadly nuisance has undergone a paradigm shift such that CO is now recognized as a neurotransmitter and viable pharmaceutical candidate. This review is intended to provide a brief history on the trace origins pertaining to endogenous formation and therapeutic application of CO.

Historical review: the carbon monoxide diffusing capacity (DLCO) and its membrane (DM) and red cell (Theta.Vc) components.

The single breath carbon monoxide diffusing capacity (DLCO sb), also called the transfer factor (TLCO), was introduced by Marie and August Krogh in two papers (Krogh and Krogh, Skand. Arch. Physiol. 23, 236-247, 1909; Krogh, J. Physiol., Lond. 49, 271-296, 1915). Physiologically, their measurements showed that sufficient oxygen (by extrapolation from CO) diffused passively from gas to blood without the need to postulate oxygen secretion, a popular theory at the time. Their DLCO sb technique was neglected until the advent of the infra-red CO meter in the 1950s. Ogilvie et al., J. Clin. Invest. 36, 1-17, 1957 published a standardized technique for a 'modified Krogh' single breath DLCO, which eventually became the method of choice in pulmonary function laboratories. The Roughton-Forster equation (J. Appl. Physiol. 1957, 11, 290-302) was an important step conceptually; it partitioned alveolar-capillary diffusion of oxygen (O2) and carbon monoxide (CO) into a membrane component (DM) and a red cell component (theta.Vc) where theta is the DLCO (or DL(O2)) per ml of blood (measured in vitro), and Vc is the pulmonary capillary volume. This equation was based on the kinetics of O2 and CO with haemoglobin (Hb) in solution and with whole blood Hartridge and Roughton, Nature, 1923, 111, 325-326; Proc. R. Soc. Lond. Ser. A, 1923, 104, 376-394; (Proc. R. Soc. Lond. Ser. B, 1923, 94, 336-367; Proc. R. Soc. Lond. Ser. A 1923, 104, 395-430; J. Physiol., Lond. 1927, 62, 232-242; Roughton, Proc. R. Soc. Lond. Ser. B 1932, 111, 1-36) and on the relationship between alveolar P(O2) and 1/DLCO. Subsequently, the relationship between DL(O2) (Lilienthal et al., Am. J. Physiol. 147, 199-216, 1946) and DL(CO) was defined. More recently, the measurement of the nitric oxide diffusing capacity (DLNO) has been introduced. For DL(O2) and DLNO the membrane component (as 1/DM) is an important part of the overall diffusion (transfer) resistance. For the DLCO, 1/theta.Vc probably plays the greater role as the rate limiting step. A crucial question, the effect of unstirred plasma layers on the 'true' value of thetaCO in vivo, has not been resolved, but this does not detract from the clinical role of the DLCO sb (TLCO) as an essential test of lung function.