The pulmonary diffusing capacity for nitric oxide (DL,NO), also called the transfer factor of the lung for nitric oxide (TL,NO), is a pulmonary function measurement that quantifies the rate of uptake of inhaled nitric oxide (NO) from the alveolar gas into the pulmonary capillary blood. It is expressed in units of mL·min−1·mmHg−1 (traditional) or mmol·min−1·kPa−1 (SI), with the conversion factor being division by 2.985. Because NO reacts with haemoglobin roughly 1,500 times faster than carbon monoxide (CO), DL,NO is weighted toward the alveolar–capillary membrane component of gas transfer (DM), in contrast to DL,CO, which is dominated by the red cell or blood component (θCO·VC). When measured simultaneously with DL,CO, the combined single-breath DL,NO–DL,CO technique allows partitioning of total pulmonary gas transfer resistance into its membrane (DM) and microvascular (θ·VC) components using the Roughton–Forster equation. The test was first performed in 1983 and has been the subject of a 2017 European Respiratory Society (ERS) technical standards document that standardised its measurement methodology, equipment specifications, quality control requirements, and reference equations for clinical use.
History
Origins in Cambridge Early research on nitric oxide in the United Kingdom was directed toward its toxicology rather than its physiology. In the late 1970s, "oxides of nitrogen" were suspected as a cause of lung disease from atmospheric pollution, indoor air pollution, and cigarette smoke. High concentrations of NO (over 100 parts per million) and lower doses of nitrogen dioxide (NO2; 25 ppm) were known to cause lung damage in cases of accidental human exposure or experimental animal exposure. An emphysema-like lesion had been described in laboratory rats exposed to nitrogen oxides, fuelling speculation that these compounds caused emphysema in smokers. At that time, the tobacco industry was under pressure to produce a "safer cigarette." To investigate NO in cigarette smoke, scientists at British American Tobacco constructed a prototype NO gas analyser based on chemiluminescence, a technique described by Brian Thrush and colleagues in 1964. The analyser generated ozone from atmospheric oxygen and reacted it with the gas sample; any NO was immediately converted to NO2 in an excited state, which emitted photons of light upon returning to the ground state. This highly sensitive and specific method has underpinned most subsequent work on pulmonary NO uptake. Tim Higenbottam at Cambridge collaborated with British American Tobacco, who loaned him their analyser. Higenbottam and colleagues had previously failed to demonstrate a relationship between smokers' cigarette tar yields and airflow obstruction prevalence, and concluded that attention should be paid to the gas-phase constituents of smoke, principally CO and NO. Colin Borland's doctoral project was to compare NO and CO uptake using the chemiluminescent analyser for NO alongside a commercial infrared CO analyser with a helium analyser. He initially examined 40 ppm—a concentration he had (erroneously) calculated to be the alveolar NO level during inhalation of a popular UK cigarette brand. Borland found that NO uptake only occurred when volumes exceeding the dead space were inhaled. The first measurements of DL,NO (reported as TL,NO) were presented by Borland, Chamberlain and Higenbottam to the UK Medical Research Society in Spring 1983. The suggestion to measure the transfer factor came from their technician, Andrew Chamberlain (subsequently Professor of Bioarchaeology at the University of Manchester). They found that KNO (the rate constant for alveolar NO uptake) was highly correlated with but exceeded KCO four- to five-fold, and like KCO, increased with exercise. In a subsequent abstract, they calculated DM assuming θNO to be infinite. The full paper, containing observations on varying breathhold time, undetectable back tension, greater volume dependence of DL,NO than DL,CO, and independence from hyperoxia, was published in 1989. Regarding the original hypothesis, it is now considered very unlikely that NO in cigarette smoke causes emphysema: the half-life of oxidation of NO in air is approximately one hour, compared to roughly two seconds for alveolar uptake. Furthermore, histological NO2-induced emphysema in rats differs markedly from smokers' emphysema, and large international differences in cigarette NO yields do not parallel emphysema incidence.
The French connection The Bordeaux contribution arose independently, a positive side-effect of the May 1968 events in Paris. Professor Daniel Bargeton, Hervé Guénard's mentor, was vice-dean of the Paris medical faculty. When the university came to a standstill during the social upheaval, he returned to research and conceived the idea of calculating DM,CO and VC using two transfer gases in a single manoeuvre. He initially proposed using CO and hydrogen sulphide (H2S), but this gas proved highly problematic: its odour was objectionable, it deposited sulphur in mass spectrometer ionisation chambers, and it was too soluble in water, disappearing rapidly into the airway walls. After arriving in Bordeaux in 1979, Guénard systematically reviewed a list of candidate gases from a chemistry textbook. Sulphur compounds largely shared the same drawbacks; the list of nitrogen oxides was shorter, and the choice of NO was straightforward since other oxides such as N2O2 and NO2 did not meet specifications. Guénard reasoned that the equation 1/DL = 1/DM + 1/(θ·VC) could be solved by a single-breath manoeuvre using CO and NO simultaneously. The Bordeaux group published their formula for DM and VC from a combined single-breath DL,NO and DL,CO in 1987. Importantly, among their references was a 1958 paper by Carlsen and Comroe who had measured the rate constant for the reaction of NO with red cells in the absence of oxygen using the same rapid-reaction apparatus that Forster had used for CO. Two other significant developments occurred in 1987: two independent groups proved that NO was identical to Endothelium-Derived Relaxing Factor (EDRF), enormously increasing scientific interest in NO; and Forster made further measurements of θCO at physiological pH, obtaining values that yielded slightly lower VC and rather larger DM compared to his 1957 data.
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