Recent progress on anti-nociceptive effects of carbon monoxide releasing molecule-2 (CORM-2).

The role of carbon monoxide (CO) has evolved albeit controversial disputes on its toxicity. This biological gasotransmitter participates in the endogenous regulation of neurotransmitters and neuropeptides released in the nervous system. Exogenous CO gas inhalation at a lower concentration has been the subject of investigations, which have revealed its biological homeostatic mechanisms and protective effects against many pathological conditions. This therapeutic procedure of CO is, however, limited due to its immediate release, which favours haemoglobin at a high affinity with the subsequent generation of toxic carboxyhaemoglobin in tissues. In order to address this problem, carbon monoxide releasing molecule-2 (CORM-2) or also known as tricarbonyldichlororuthenium II dimer is developed to liberate a controlled amount of CO in the biological systems. In this review, we examine several potential mechanisms exerted by this therapeutic compound to produce the anti-nociceptive effect that has been demonstrated in previous studies. This review could shed light on the role of CORM-2 to reduce pain, especially in cases of chronic and neuropathic pain.

An assessment of post-COVID-19 infection pulmonary functions in healthcare professionals.

BACKGROUND: The medium- and long-term effects of COVID-19 infection on pulmonary function are still unknown. The present study aimed to investigate the pulmonary functions in healthcare professionals who had persistent complaints after contracting COVID-19 and returning to work. METHODS: The study included COVID-19-infected healthcare professionals from the Düzce University Medical Faculty Hospital who volunteered to participate. Medical histories, medical records, pulmonary function tests, the diffusing capacity of the lungs for carbon monoxide (DLCO) test, and the 6-minute walk test (6MWT) were used to collect data from all participants. RESULTS: The study included 53 healthcare professionals, with an average age of 38 ± 10 years (min: 24 years and max: 71 years), including 29 female (54.7%) and 24 male (45.3%) participants. Of the participants, 22.6% were smokers, 35.8% (19 individuals) had comorbidities, and 17% (9 individuals) were hospitalized. The mean length of stay was 9 ± 4 days (mean ± standard deviation). The most prevalent symptoms were weakness (88.7%), muscle aches (67.9%), inability to smell/taste (60.4%), headache (54.7%), fever (45.3%), cough (41.5%), and shortness of breath (37.7%). The mean time to return to work after a positive polymerase chain reaction (PCR) test for COVID-19 was 18 ± 13 days. The average time among post-disease pulmonary function, 6MW, and DLCO tests was 89 ± 36 days (min: 15 and max: 205). The DLCO level decreased in 39.6% (21) of the participants. Female participants had a significantly higher rate of decreased DLCO levels than male participants (25% vs. 55.2%, P = .026). DLCO levels were significantly higher in participants with long-term persistent complaints (P = .043). The later the time to return to work, the lower the DLCO value (r = -0.290 and P = .035). The 6MWT distance was positively correlated with hemoglobin and lymphocyte levels at the time of the disease onset and negatively correlated with D-dimer levels. The most prevalent symptoms during the control visits were shortness of breath/effort dyspnea (24.6%), weakness (9.5%), and muscle aches (7.6%). CONCLUSION: Significant persistent complaints (47.2%) and low DLCO levels (39.6%) were observed in healthcare professionals during control visits at a mean time of 3 months after the COVID-19 infection. Symptoms and spirometry measurements, including DLCO, may be helpful in the follow-up of healthcare professionals who contracted COVID-19. Further comprehensive studies with long-term follow-up periods are required.

The association between transfer coefficient of the lung and the risk of exacerbation in asthma-COPD overlap: an observational cohort study.

BACKGROUND: Asthma-chronic obstructive pulmonary disease (COPD) overlap (ACO) patients experience exacerbations more frequently than those with asthma or COPD alone. Since low diffusing capacity of the lung for carbon monoxide (DLCO) is known as a strong risk factor for severe exacerbation in COPD, DLCO or a transfer coefficient of the lung for carbon monoxide (KCO) is speculated to also be associated with the risk of exacerbations in ACO. METHODS: This study was conducted as an observational cohort survey at the National Hospital Organization Fukuoka National Hospital. DLCO and KCO were measured in 94 patients aged ≥ 40 years with a confirmed diagnosis of ACO. Multivariable-adjusted hazard ratios (HRs) for the exacerbation-free rate over one year were estimated and compared across the levels of DLCO and KCO. RESULTS: Within one year, 33.3% of the cohort experienced exacerbations. After adjustment for potential confounders, low KCO (< 80% per predicted) was positively associated with the incidence of exacerbation (multivariable-adjusted HR = 3.71 (95% confidence interval 1.32-10.4)). The association between low DLCO (< 80% per predicted) and exacerbations showed similar trends, although it failed to reach statistical significance (multivariable-adjusted HR = 1.31 (95% confidence interval 0.55-3.11)). CONCLUSIONS: Low KCO was a significant risk factor for exacerbations among patients with ACO. Clinicians should be aware that ACO patients with impaired KCO are at increased risk of exacerbations and that careful management in such a population is mandatory.

Heme oxygenase-1/carbon monoxide signaling participates in the accumulation of triterpenoids of Ganoderma lucidum.

Ganoderic triterpenoids (GTs) are the primary bioactive constituents of the Basidiomycotina fungus, Ganoderma lucidum. These compounds exhibit antitumor, anti-hyperlipidemic, and immune-modulatory pharmacological activities. This study focused on GT accumulation in mycelia of G. lucidum mediated by the heme oxygenase-1 (HO-1)/carbon monoxide (CO) signaling. Compared with the control, hemin (10 µmol/L) induced an increase of 60.1% in GT content and 57.1% in HO-1 activity. Moreover, carbon monoxide-releasing molecule-2 (CORM-2), CO donor, increased GT content by 56.0% and HO-1 activity by 18.1%. Zn protoporphyrin IX (ZnPPIX), a specific HO-1 inhibitor, significantly reduced GT content by 26.0% and HO-1 activity by 15.8%, while hemin supplementation reversed these effects. Transcriptome sequencing showed that HO-1/CO could function directly as a regulator involved in promoting GT accumulation by regulating gene expression in the mevalonate pathway, and modulating the reactive oxygen species (ROS) and Ca2+ pathways. The results of this study may help enhance large-scale GT production and support further exploration of GT metabolic networks and relevant signaling cross-talk.

Prognostic marker for severe acute exacerbation of chronic obstructive pulmonary disease: analysis of diffusing capacity of the lung for carbon monoxide (DLCO) and forced expiratory volume in one second (FEV1).

BACKGROUND: It is important to assess the prognosis of patients with chronic obstructive pulmonary disease (COPD) and acute exacerbation of COPD (AECOPD). Recently, it was suggested that diffusing capacity of the lung for carbon monoxide (DLCO) should be added to multidimensional tools for assessing COPD. This study aimed to compare the DLCO and forced expiratory volume in one second (FEV1) to identify better prognostic factors for admitted patients with AECOPD. METHODS: We retrospectively analyzed 342 patients with AECOPD receiving inpatient treatment. We classified 342 severe AECOPD patients by severity of DLCO and FEV1 (≤ vs. > 50% predicted). We tested the association of FEV1 and DLCO with the following outcomes: in-hospital mortality, need for mechanical ventilation, need for intensive care unit (ICU) care. We analyzed the prognostic factors by multivariate analysis using logistic regression. In addition, we conducted a correlation analysis and receiver operating characteristic (ROC) curve analysis. RESULTS: In multivariate analyses, DLCO was associated with mortality (odds ratio = 4.408; 95% CI 1.070-18.167; P = 0.040) and need for mechanical ventilation (odds ratio = 2.855; 95% CI 1.216-6.704; P = 0.016) and ICU care (odds ratios = 2.685; 95% CI 1.290-5.590; P = 0.008). However, there was no statistically significant difference in mortality rate when using FEV1 classification (P = 0.075). In multivariate linear regression analyses, DLCO (B = - 0.542 ± 0.121, P < 0.001) and FEV1 (B = - 0.106 ± 0.106, P = 0.006) were negatively associated with length of hospital stay. In addition, DLCO showed better predictive ability than FEV1 in ROC curve analysis. The area under the curve (AUC) of DLCO was greater than 0.68 for all prognostic factors, and in contrast, the AUC of FEV1 was less than 0.68. CONCLUSION: DLCO was likely to be as good as or better prognostic marker than FEV1 in severe AECOPD.

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.

Pulmonary diffusing capacity measured by NO/CO transfer in Tunisian boys.

BACKGROUND: The diffusing capacity, which measures gas-exchange, uses reference values based on data from American or European studies. There are currently no reference values of pulmonary diffusing capacity (TL) and its components, such as the conductance of the membrane (Dm) and capillary lung volume (Vc) for healthy North African children. OBJECTIVES: We determined the prediction equations-reference values for TL, Dm, Vc and the alveolar volume (VA) in healthy Tunisian boys. METHODS: Values of Vc, Dm, TL, and VA were measured by the NO/CO transfer method, using a single breath maneuver in 118 Tunisian boys (8-14 years old) at rest. We performed linear regression analysis of the pulmonary parameters and independent variables, such as height, weight, and age. RESULTS: The reference equations for pulmonary diffusing capacity for carbon monoxide (TLCO ) was 0.201 × weight (kg) + 8.979; for TLNO was 0.76 × height (cm)-24.383; for Dm was 0.388 × height (cm)- 12.555 and for VA was 0.34 × height (cm)-3.951. Vc increased significantly with weight (P < .05) but not with age (P > .05). CONCLUSIONS: References norms for TLCO and TL for nitric oxide and its components in young Tunisian boys are similar to data from other countries. The prediction equations we developed can be extended to clinical practice in Tunisia and can be considered for use in neighboring North African countries.

Lung function in men with and without HIV.

OBJECTIVES: Initial studies suggest HIV-positive persons may be at increased risk for chronic lung diseases such as chronic obstructive pulmonary disease, but have commonly relied on single-center designs, lacked HIV-negative controls, or assessed lung function with only spirometry. We tested differences in spirometry and single-breath diffusing capacity for carbon monoxide (DLCO) in persons with and without HIV. DESIGN: Cross-sectional, observational study. METHODS: Participants were enrolled from the Multicenter AIDS Cohort Study, a longitudinal cohort study of men who have sex with men (both HIV-positive and HIV-negative) at four sites in the United States. Standardized spirometry and DLCO testing were performed in all eligible, consenting participants at routine study visits. We tested associations between HIV status and spirometry and DLCO results, using linear and logistic regression. RESULTS: Among 1067 men, median age was 57 years, prevalence of current marijuana (30%), and cigarette (24%) use was high, and another 45% were former cigarette smokers. Median forced expiratory volume in 1 s was 97% of predicted normal and DLCO was 85% of predicted normal. HIV-positive persons demonstrated no statistical difference in forced expiratory volume in 1 s compared with HIV-negative persons, but had worse DLCO (adjusted difference -2.6% of predicted; 95% confidence interval: -4.7 to -0.6%) and a higher risk of DLCO impairment (odds ratio for DLCO < 60% of predicted 2.97; 95% confidence interval: 1.36-6.47). Lower DLCO was associated with lower nadir CD4 cell counts. CONCLUSION: HIV-positive men are at increased risk of abnormal gas exchange, indicated by low DLCO, compared with men without HIV.

Heme Oxygenase-1 and Carbon Monoxide Regulate Growth and Progression in Glioblastoma Cells.

In human glioma tumours, heme oxygenase-1 (HO-1) is overexpressed when compared with normal brain tissues and during oligodendroglioma progression. However, the molecular mechanisms mediated by HO-1 to promote glioblastoma remain unknown. We therefore aimed at investigating the effect of HO-1 expression and its selective enzymatic inhibition in two different cell lines (i.e. A172 and U87-MG). HO-1 was induced by hemin treatment (10 µM), and VP13/47 (100 µM) was used as a specific non-competitive inhibitor of HO-1 activity. Cell proliferation was measured by cell index measurement (xCelligence technology) and clonogenic assay, whereas cell migration was assessed by wound healing assay. Carbon monoxide-releasing molecules (CORMs) (i.e. CORM-3 and CORM-A1) were also used in a separate set of experiments to confirm the effect of HO-1 by-product in glioblastoma progression further. Our results were further validated using GSE4412 microarray dataset analysis and comparing biopsies overexpressing HO-1 with the rest of the cases. Our results showed that hemin was able to induce both HO-1 gene and protein expression in a cell-dependent manner being A172 more responsive to pharmacological upregulation of HO-1. Hemin, but not CORMs treatment, resulted in a significant increase of cell proliferation following 24 h of treatment as measured by increased cell index and colony formation capacity and such effect was abolished by VP13/47. Interestingly, both hemin and CORMs showed a significant effect on the wound healing assay also exhibiting cell specificity. Finally, our dataset analysis showed a positive correlation of HO-1 gene expression with ITGBI and ITGBII which are membrane receptors involved in cell adhesion, embryogenesis, tissue repair, immune response and metastatic diffusion of tumour cells. In conclusion, our data suggest that HO-1 and its by-product CO exhibit a cell-specific effect on various aspects of disease progression and are associated with a complex series of molecular mechanisms driving cell proliferation, survival and metastasis.

Maternal disease and gasotransmitters.

The three known gasotransmitters, nitric oxide, carbon monoxide, and hydrogen sulfide are involved in key processes throughout pregnancy. Gasotransmitters are known to impact on smooth muscle tone, regulation of immune responses, and oxidative state of cells and their component molecules. Failure of the systems that tightly regulate gasotransmitter production and downstream effects are thought to contribute to common maternal diseases such as preeclampsia and preterm birth. Normal pregnancy-related changes in uterine blood flow depend heavily on gasotransmitter signaling. In preeclampsia, endothelial dysfunction is a major contributor to aberrant gasotransmitter signaling, resulting in hypertension after 20 weeks gestation. Maintenance of pregnancy to term also requires gasotransmitter-mediated uterine quiescence. As the appropriate signals for parturition occur, regulation of gasotransmitter signaling must work in concert with those endocrine signals in order for appropriate labor and delivery timing. Like preeclampsia, preterm birth may have origins in abnormal gasotransmitter signaling. We review the evidence for the involvement of gasotransmitters in preeclampsia and preterm birth, as well as mechanistic and molecular signaling targets.

Lung Diffusing Capacities (DL ) for Nitric Oxide (NO) and Carbon Monoxide (CO): The Evolving Story.

Nitric oxide and carbon monoxide diffusing capacities (DLNO and DLCO ) obey Fick's First Law of Diffusion and the basic principles of chemical kinetic theory. NO gas transfer is dominated by membrane diffusion (DM ), whereas CO transfer is limited by diffusion plus chemical reaction within the red cell. Marie Krogh, who pioneered the single-breath measurement of DLCO in 1915, believed that the combination of CO with red cell hemoglobin (Hb) was instantaneous. Roughton and colleagues subsequently showed, in vitro, that the reaction rate was finite, and prolonged in the presence of high P O 2 . Roughton and Forster (R-F) proposed that the resistance to transfer (1/DL ) was the sum of the membrane resistance (1/DM ) and (1/θVc), the red cell resistance (θ being the CO or NO conductance for blood uptake and Vc the capillary volume). From this R-F equation, DM for CO and Vc can be solved with simultaneous NO and CO inhalation. At near maximum exercise, DMCO and Vc for normal subjects were 88% and 79%, respectively, of morphometric values. The validity of these calculations depends on the values chosen for θ for CO and NO, and on the diffusivity of NO versus CO. Recent mathematical modeling suggests that θ for NO is "effectively" infinite because NO reacts only with Hb in the outer 0.1 µM of the red cell. An "infinite θNO " recalculation reduced DMCO to 53% and increased Vc to 95% of morphometric values. © 2020 American Physiological Society. Compr Physiol 10:73-97, 2020.

Diffusing Capacity of Carbon Monoxide in Assessment of COPD.

BACKGROUND: Diffusing capacity of the lung for carbon monoxide (Dlco) is inconsistently obtained in patients with COPD, and the added benefit of Dlco testing beyond that of more common tools is unknown. OBJECTIVE: The goal of this study was to determine whether lower Dlco is associated with increased COPD morbidity independent of emphysema assessed via spirometry and CT imaging. METHODS: Data for 1,806 participants with COPD from the Genetic Epidemiology of COPD (COPDGene) study 5-year visit were analyzed, including pulmonary function testing, quality of life, symptoms, exercise performance, and exacerbation rates. Dlco percent predicted was primarily analyzed as a continuous variable and additionally categorized into four groups: (1) Dlco and FEV1 > 50% (reference); (2) only Dlco ≤ 50%; (3) only FEV1 ≤ 50%; and (4) both ≤ 50% predicted. Outcomes were modeled by using multivariable linear and negative binomial regression, including emphysema and FEV1 percent predicted among other confounders. RESULTS: In multivariable analyses, every 10% predicted decrease in Dlco was associated with symptoms and quality of life (COPD Assessment Test, 0.53 [P < .001]; St. George's Respiratory Questionnaire, 1.67 [P < .001]; Medical Outcomes Study Short Form 36 Physical Function, -0.89 [P < .001]), exercise performance (6-min walk distance, -45.35 feet; P < .001), and severe exacerbation rate (rate ratio, 1.14; P < .001). When categorized, severe impairment in Dlco alone, FEV1 alone, or both Dlco and FEV1 were associated with significantly worse morbidity compared with the reference group (P < .05 for all outcomes). CONCLUSIONS: Impairment in Dlco was associated with increased COPD symptoms, reduced exercise performance, and severe exacerbation risk even after accounting for spirometry and CT evidence of emphysema. These findings suggest that Dlco should be considered for inclusion in future multidimensional tools assessing COPD.

Incorporating Lung Diffusing Capacity for Carbon Monoxide in Clinical Decision Making in Chest Medicine.

Lung diffusing capacity for carbon monoxide (Dlco) remains the only noninvasive pulmonary function test to provide an integrated picture of gas exchange efficiency in human lungs. Due to its critical dependence on the accessible "alveolar" volume (Va), there remains substantial misunderstanding on the interpretation of Dlco and the diffusion coefficient (Dlco/Va ratio, Kco). This article presents the physiologic and methodologic foundations of Dlco measurement. A clinically friendly approach for Dlco interpretation that takes those caveats into consideration is outlined. The clinical scenarios in which Dlco can effectively assist the chest physician are discussed and illustrative clinical cases are presented.

Combined diffusing capacity for nitric oxide and carbon monoxide as predictor of bronchiolitis obliterans syndrome following lung transplantation.

BACKGROUND: There is a need for non-invasive parameters that are sensitive to the development of the bronchiolitis obliterans syndrome (BOS) in lung transplantation (LTx) patients. We studied whether the pulmonary diffusing capacity for inhaled nitric oxide is capable of detecting BOS stages. METHODS: Sixty-one LTx patients were included into this cross-sectional study (19/29/7/3/3 in BOS stages 0/0-p/1/2/3). For analysis stages 0/0-p versus 1/2/3 ("BOS binary-early"), and stages 0/0-p/1 versus 2/3 ("BOS binary-late") were summarized. Measurements of the combined diffusing capacity for nitric oxide (DLNO) and carbon monoxide (DLCO) were compared with spirometry and bodyplethysmography, and their relative importance was evaluated by discriminant analysis. RESULTS: Regarding the recognition of "BOS binary-early", among spirometric parameters forced expiratory volume in 1 s (FEV1) was best, among bodyplethysmographic parameters airway resistance, and among diffusing parameters DLNO. Regarding "BOS binary-late", DLNO was inferior to bodyplethysmographic parameters. CONCLUSION: Although the study comprised only measurements at a single time point and no follow-up, DLNO outperformed FEV1, the time course of which is used in detecting BOS. Together with its pathophysiological plausibility, this result suggests that the measurement of DLNO, possibly over time, could be an easily applicable tool for the monitoring of LTx patients and should be evaluated in larger studies.

Heme oxygenase-1/biliverdin/carbon monoxide pathway downregulates hypernociception in rats by a mechanism dependent on cGMP/ATP-sensitive K+ channels.

OBJECTIVE AND DESIGN: To investigate the role of heme oxygenase-1 (HO-1), carbon monoxide (CO), and biliverdin (BVD) in the zymosan-induced TMJ arthritis in rats. MATERIALS AND METHODS: Mechanical threshold was assessed before and 4 h after TMJ arthritis induction in rats. Cell influx, myeloperoxidase activity, and histological changes were measured in the TMJ lavages and tissues. Trigeminal ganglion and periarticular tissues were used for HO-1, TNF-α, and IL-1ß mRNA time course expression and immunohistochemical analyses. Hemin (0.1, 0.3, or 1 mg kg-1), DMDC (0.025, 0.25, or 2.5 µmol kg-1), biliverdin (1, 3, or 10 mg kg-1), or ZnPP-IX (1, 3 or 9 mg kg-1) were injected (s.c.) 60 min before zymosan. ODQ (12.5 µmol kg-1; s.c.) or glibenclamide (10 mg kg-1; i.p.) was administered 1 h and 30 min prior to DMDC (2.5 µmol kg-1; s.c), respectively. RESULTS: Hemin (1 mg kg-1), DMDC (2.5 µmol kg-1), and BVD (10 mg kg-1) reduced hypernociception and leukocyte migration, which ZnPP (3 mg kg-1) enhanced. The effects of DMDC were counteracted by ODQ and glibenclamide. The HO-1, TNF-α, and IL-1ß mRNA expression and immunolabelling increased. CONCLUSIONS: HO-1/BVD/CO pathway activation provides anti-nociceptive and anti-inflammatory effects on the zymosan-induced TMJ hypernociception in rats.

Gaseous Signaling Molecules in Cardiovascular Function: From Mechanisms to Clinical Translation.

Carbon monoxide (CO), hydrogen sulfide (H2S), and nitric oxide (NO) constitute endogenous gaseous molecules produced by specific enzymes. These gases are chemically simple, but exert multiple effects and act through shared molecular targets to control both physiology and pathophysiology in the cardiovascular system (CVS). The gases act via direct and/or indirect interactions with each other in proteins such as heme-containing enzymes, the mitochondrial respiratory complex, and ion channels, among others. Studies of the major impacts of CO, H2S, and NO on the CVS have revealed their involvement in controlling blood pressure and in reducing cardiac reperfusion injuries, although their functional roles are not limited to these conditions. In this review, the basic aspects of CO, H2S, and NO, including their production and effects on enzymes, mitochondrial respiration and biogenesis, and ion channels are briefly addressed to provide insight into their biology with respect to the CVS. Finally, potential therapeutic applications of CO, H2S, and NO with the CVS are addressed, based on the use of exogenous donors and different types of delivery systems.

An alternative method to measure the diffusing capacity of the lung for carbon monoxide in infants.

BACKGROUND: Lung diffusion assessed by the uptake of carbon monoxide (DLCO ) and alveolar volume (VA ) by inert gas dilution are readily assessed in cooperative older subjects; however, obtaining these measurements in infants has been much more difficult. Our laboratory has measured DLCO and VA in sleeping infants using a mass spectrometer, which continuously measures gas concentrations, and demonstrated that infants with bronchopulmonary dysplasia (BPD) have lower DLCO , but no difference in VA compared to full-term controls. The mass spectrometer is expensive and lacks portability; therefore, we evaluated whether measurement of end-expiratory alveolar gas concentrations using a gas chromatograph would provide an alternative approach. METHODS: (1) Using our previously digitized data for infants with BPD and full-term controls, DLCO and VA were calculated at end-expiration rather than between 60 and 80% of expired volume, as previously reported. (2) In a new group of infants, DLCO and VA were measured using gas concentrations obtained at end-expiration with a mass spectrometer and a gas chromatograph. RESULTS: (1) Using end-expiratory concentrations, infants with BPD (n = 49) had significantly lower DLCO , but similar VA compared to healthy controls (n = 34) (DLCO : 4.2 vs 4.6 mL/min/mmHg, P = 0.047; VA : 614 vs 608 mL, P = 0.772). (2) Among newly evaluated infants (n = 28), DLCO and VA obtained with a mass spectrometer and a gas chromatograph were highly correlated (R2 = 0.94 and 0.99, respectively), and were not significantly different for the two analyzers. CONCLUSION: Measuring DLCO and VA at end-expiration using a gas chromatograph can provide an effective assessment of gas exchange in sleeping infants.

Pulmonary Vascular Function and Aerobic Exercise Capacity at Moderate Altitude.

PURPOSE: There has been suggestion that a greater "pulmonary vascular reserve" defined by a low pulmonary vascular resistance (PVR) and a high lung diffusing capacity (DL) allow for a superior aerobic exercise capacity. How pulmonary vascular reserve might affect exercise capacity at moderate altitude is not known. METHODS: Thirty-eight healthy subjects underwent an exercise stress echocardiography of the pulmonary circulation, combined with measurements of DL for nitric oxide (NO) and carbon monoxide (CO) and a cardiopulmonary exercise test at sea level and at an altitude of 2250 m. RESULTS: At rest, moderate altitude decreased arterial oxygen content (CaO2) from 19.1 ± 1.6 to 18.4 ± 1.7 mL·dL, P < 0.001, and slightly increased PVR, DLNO, and DLCO. Exercise at moderate altitude was associated with decreases in maximum O2 uptake (V˙O2max), from 51 ± 9 to 43 ± 8 mL·kg⋅min, P < 0.001, and CaO2 to 16.5 ± 1.7 mL·dL, P < 0.001, but no different cardiac output, PVR, and pulmonary vascular distensibility. DLNO was inversely correlated to the ventilatory equivalent of CO2 (V˙E/V˙CO2) at sea level and at moderate altitude. Independent determinants of V˙O2max as determined by a multivariable analysis were the slope of mean pulmonary artery pressure-cardiac output relationship, resting stroke volume, and resting DLNO at sea level as well as at moderate altitude. The magnitude of the decrease in V˙O2max at moderate altitude was independently predicted by more pronounced exercise-induced decrease in CaO2 at moderate altitude. CONCLUSION: Aerobic exercise capacity is similarly modulated by pulmonary vascular reserve at moderate altitude and at sea level. Decreased aerobic exercise capacity at moderate altitude is mainly explained by exercise-induced decrease in arterial oxygenation.

Inhaled Carbon Monoxide: From Toxin to Therapy.

Carbon monoxide (CO) is usually recognized as a toxic gas that can be used to assess lung function in the pulmonary function laboratory. The toxicity of CO relates to its high affinity for hemoglobin and other heme molecules, producing carboxyhemoglobin (HbCO). Despite that blood HbCO levels are commonly measured in patients with CO poisoning, the clinical presentation often does not correlate with the HbCO level, and clinical improvement in the patient's condition does not correlate with HbCO clearance. In patients with CO poisoning, administration of 100% O2 is standard practice. If available, hyperbaric O2 can be used, although this is controversial. Measurement of exhaled CO might be useful to estimate HbCO, such as in smoking cessation programs, but assessment of HbCO using pulse oximetry can be misleading. Endogenous CO is generated as the result of heme oxygenase activity. It is becoming increasingly recognized that the results of heme oxygenase activity, specifically CO production, might have important physiologic functions. These include effects on vascular function, inflammation, apoptosis, cell proliferation, and signaling pathways. Given the abundance of basic science supporting a therapeutic role for CO, clinical trials are exploring this potential.