Tetsuro Yokoyama

Distribution of ventilation and of diffusing capacity to perfusion in the lung

We developed a method for estimating the distribution of ventilation (VA) and of diffusing capacity (G) to perfusion (Q) in the lungs. We used O2, CO2 and CO together with six inert gases of widely differing solubility and assumed that mass transfer efficiency of each gas in a gas exchange unit is limited by both VA/Q and G/Q ratios. The underlying lung model comprised 20 units along both the VA/Q and G/Q axes. Using numerical analysis, we transformed the data into a virtually continuous distribution of Q in the VA/Q-G/Q field. We tested the precision of the numerical procedure by examining the recovery of various artificial distributions, and found that distributions with up to two modes could be recovered with reasonable accuracy. Analytical results from 15 patients with interstitial pneumonia of unknown etiology (IPF) revealed the following features. (1) In an early disease stage, most of the lung was operating in the range of normal VA/Q, without a significant contribution of diffusion limitation. (2) An advanced stage of the disease exhibited a widening of VA/Q distribution and either broad unimodal or bimodal distribution of G/Q, extending to G/Q below 10(-3) ml (STPD)/(ml.Torr) with diffusion-limited O2 exchange. (3) Severe diffusion limitation causing disequilibrium of inert gas across the blood-gas barrier was observed in three (far advanced fibrosis; active interstitial inflammation) out of 15 patients. These findings suggest that inhomogeneity of G/Q does exist and may play an appreciable role in causing impairment of gas exchange in patients with interstitial pneumonia.

Regulation of Blood Flow in Pulmonary Microcirculation by Vasoactive Arachidonic Acid Metabolites – Analysis in Acute Lung Injury

In order to assess the physiological abnormalities and the pathogenesis of adult respiratory distress syndrome (ARDS), especially that associated with pulmonary fat embolism, acute lung injury caused by monounsaturated nonsterified fat oleic acid (cis-9-octadecenoic acid) has been widely used in animal experiments. This lung injury results in an extensive, multifocal, and heterogeneously distributed lung damage with alveolar flooding, interstitial edema and microatelectasis. The ability to reduce the perfusion entering into damaged and edematous areas is essentially important in preserving blood oxygenation in ARDS.

Estimation of the distribution profile of airway resistance in the lungs

The distribution profile of resistance in a series lung model consisting of airways of 23 generations with alveoli was estimated in 10 healthy subjects and 7 subjects with chronic pulmonary emphysema. Forced oscillation was applied to the subjects at the mouth using a complex wave composed of sine waves at frequencies through the range 4 to 20 Hz in 1-Hz steps. The pleural pressure was measured with a catheter-tip micromanometer, which was installed in an esophageal balloon. The frequency dependency of the pulmonary impedance was analyzed using a penalty function method, and a stable estimate of the distribution profile of resistance in the lungs was thus obtained. The central airway resistance (defined as the resistance from generation 0 to generation 7) was estimated as 1.18 +/- 0.37 cm H2O/liter/sec in the healthy subjects and 1.03 +/- 1.13 cm H2O/liter/sec in the subjects with chronic pulmonary emphysema. The peripheral airway resistance (defined as the resistance from generation 8 to generation 23) was estimated as 0.06 +/- 0.03 cm H2O/liter/sec in the healthy subjects and 6.38 +/- 3.77 cm H2O/liter/sec in the subjects with chronic pulmonary emphysema.

Influences of Carbon Monoxide on the Binding of Oxygen, Carbon Dioxide, Proton and 2,3-Diphosphoglycerate to Human Hemoglobin

In an attempt to estimate the influences of CO on the CO2 Bohr effect and the 2,3-diphosphoglycerate (DPG) effect linked to the reversible binding of O2 to the hemoglobin molecule (Hb), O2 dissociation curves of human blood in the presence of CO were investigated at 37 degrees C over a DPG concentration ranging from 2.2 to 4.3 mmol/(1RBC) and a pH range of 7.2 to 7.6. The sample with a low DPG concentration was made by incubating whole blood for 6 hrs, whereas the saturation of Hb with CO, SCO in the sample was adjusted by anaerobically mixing completely carboxygenated blood with that free of O2 and CO so as to give the final SCO at either 0, 10, 15, 20, 40 or 50%. The blood samples thus prepared were diluted at 1:100 in isotonic buffer solution and were equilibrated with gas mixtures containing O2 ranging from 1 to 9% and CO2 from 4 to 9%. The SO2 and SCO values of diluted red cell suspensions were examined by means of a dual-wavelength spectrophotometric method based on the isosbestic points for reduced Hb, HbO2 and HbCO. The extinction difference at 562.7 and 578.0 nm was monitored as a measure of SO2, while that at 570.1 and 584.6 nm was recorded for determining SCO. Fitting the experimental results by the Hill equation, the coefficients describing allosteric interaction induced by CO2 hydration and by DPG in the presence of both O2 and CO were calculated for the total saturation, ST defined as the sum of SO2 and SCO, ranging from 20 to 90%.(ABSTRACT TRUNCATED AT 250 WORDS)

Attenuation of Hypoxic Pulmonary Vasoconstriction in Acute Oleic Acid Lung Injury — Significance of Vasodilator Prostanoids

To assess a significant role of hypoxic pulmonary vasoconstriction, HPV, on maintaining the gas exchange efficiency in acute lung injury, 24 mongrel dogs were treated with intravenously injecting 0.07 ml/kg of oleic acid. Hemodynamic and gas-exchange parameters were investigated at varied inspired O2 concentration, FIO2. To know a possible contribution of vasoactive prostanoids in regulating vascular reactivity under these circumstances, observations were repeated after infusion of indomethacin. The impairment of gas exchange in injured lungs was examined by measuring the fractional retention, R, of the gas in arterial blood. For this evaluation, a normal saline containing five foreign inert gases such as sulfur hexafluoride, SF6, ethane, cyclopropane, halothane and diethyl ether was infused at a constant rate through a peripheral vein. After a steady state was established, the expired gas was collected and the samples of both arterial and mixed venous blood were simultaneously taken for the inert-gas analysis. The concentrations of the indicator gases in the samples were measured in terms of a gas chromatograph equipped with an electron capture detector for SF6 and a flame ionization detector for the other four gases. Although pulmonary vascular resistance, PVR, after injecting oleic acid at FIO2 0.60 was significantly smaller than that obtained at FIO2 0.21, cardiac output, QT as well as extravascular lung water were not different between the two conditions. R value for the indicator gas was consistently lower at FIO2 0.60 irrespective of the gas species. As increasing FIO2, R estimate concerning SF6, RSF6, rational index of the fractional blood flow perfusing shunt area, decreased significantly. Administration of indomethacin caused the rise in PVR without an appreciable change in either QT or extravascular lung water but a considerable diminution in R value for the inert gas. RSF6 after infusion of indomethacin decreased from 0.35 to 0.27, accompanied by a significant rise in arterial PO2 from 84 to 99 Torr. The findings are highly compatible with the idea that HPV is distinctly attenuated in diseases areas induced by oleic acid probably due to a local accumulation of vasodilator prostanoids. Inhibiting prostanoid biosynthesis may selectively enhance the vascular reactivity to O2 in shunt vessels and may redistribute the perfusion from shunt to relatively normal areas, thereby improving gas exchange at alveolar region without altering the total amount of extravascular lung water.

Continuous Distributions of Ventilation and Gas Conductance to Perfusion in the Lungs

Theoretical analysis and experimental observations were conducted to establish a method allowing to demonstrate the characteristics of distribution of ventilation (VA) as well as of diffusive conductance (G) to perfusion (Q) in the lungs. O2, CO2 and CO binding to hemoglobin molecules within the erythrocyte together with six inert gases including SF6, ethane, cyclopropane, halothane, diethyl ether and acetone, of varied solubility in blood and different diffusivity in lung tissue, were used as indicator gases. 15 patients with interstitial pneumonia of unknown etiology, placed in the supine position, were given a mixture of 21% O2 and 0.1% CO in N2 as the inspired gas and saline containing appropriate amount of the six inert gases was infused via an antecubital vein. After a steady state was established, the expired gas was collected and the samples of both arterial and mixed venous blood were simultaneously taken through catheters inserted into the femoral and pulmonary artery. The concentrations of the indicator gases in the samples were measured by gas chromatography, with electrodes or with the Scholander gas analyzer. Assuming that the mass transfer efficiency of a given indicator gas at each gas exchange unit would be limited by VA/Q and G/Q ratios, the data obtained from the human subjects were analyzed in terms of a lung model having 20 units along the VA/Q and G/Q axes, respectively. The numerical analysis including the procedure of simultaneous Bohr integration for O2, CO2 and CO in a pulmonary capillary and the method of weighted least-squares combined with constrained optimization permitted the data to be transformed into a virtually continuous distribution of Q against VA/Q and G/Q axes. The numerical procedure was strictly tested using various artificial distributions of VA/Q and G/Q ratios, showing that it could characterize the distributions containing up to at least two modes on VA/Q-G/Q field with a substantial accuracy. Analytical results estimated from the patients with interstitial lung disease revealed the following features. (1) There appears to be bimodal distribution of Q along G/Q axis extending to relatively low G/Q less than 10(-3) ml(STPD)/(ml.Torr), which may limit O2 exchange between alveolar gas and capillary blood. This area of low G/Q receives 10% of total Q. (2) Severe diffusion limitation causing disequilibrium of the inert gas across the blood-gas barrier is solely observed in 2 out of 15 patients and an amount of Q associated with this phenomenon is very small (below 1%).(ABSTRACT TRUNCATED AT 400 WORDS)

Roles of antioxidant enzymes in erythrocytes on hypoxic pulmonary vasoconstriction

Hypoxie pulmonary vasoconstriction (HPV) is of importance in egulating the distribution of blood flow in the lung, thus allowing the lung to maintain a pertinent matching between ventilation and blood flow. Recently, several authors (cf. Archer et al, 1989b) have reported that endogenous products of reactive O2 species (ROS) in the lung are the important factor for initiating HPV.

Effects of SO2 and pH on Blood-Gas Partition Coefficients of Inert Gases

Potential effects of SO2 and of pH on blood-gas partition coefficients, lambda, for inert gases, including SF6, ethane, cyclopropane, halothane, diethyl ether, acetone and N2, were systematically investigated using human blood. Measurements on lambda were performed at 37 degrees C in conditions of varied SO2 and pH using gas chromatography. Incorporating the experimental data on lambda, multiple inert gas elimination was applied to 18 patients with varied chronic lung diseases, in order to estimate the effects of SO2 and of pH on both inert gas exchange and resultant recovery of VA/Q distribution in the lung. For this purpose, the data obtained by the procedure of multiple inert gas elimination were analyzed with the classical approach but allowance was made for lambda of the indicator gas to vary according to exchange of O2 and of CO2 in the pulmonary capillary. Among the gases studied, ethane, cyclopropane, halothane and diethyl ether showed significantly smaller lambda values in the oxygenated blood than in deoxygenated blood, whereas SF6, acetone and N2 were little dependent on SO2. An increase in lambda was found for ethane and a decrease for halothane with increasing pH in the blood. The other gases were not significantly influenced by pH. In spite of these experimental findings, regional difference of either SO2 or pH in the lung did not exert important influence on the inert gas exchange or on the predicted VA/Q distribution. In conclusion, blood-gas partition coefficients of some inert gases are consistently altered by SO2 and pH, but their possible effects on inert gas exchange seem to be negligible.

PLEURAL EFFUSION-THE DIAGNOSTIC CLUE TO A PRIMARY HYPERPARATHYROIDISM PRESENTING AS CHRONIC RELAPSING PANCREATITIS AND NEPHROLITHIASIS

胸水貯留が診断の契機となり,膵石と膵のう胞を伴う慢性再発性膵炎および腎結石を合併した原発性副甲状腺機能亢進症を術前に診断し,縦隔内腺腫を摘出し得た1例を経験したので報告する.症例は35才の男.昭和51年11月より左季肋部痛が繰り返し出現した.昭和52年4月と10月に左側胸部痛を認め胸水を指摘され11月に入院した.胸水は血性滲出性でアミラーゼは30,200SUで血清,尿アミラーゼも高値を示した.アイソザイムはいずれも膵由来であつた. ERCPで膵石症と膵のう胞を認め慢性再発性膵炎と診断した.またIVPで右腎結石を認めた.血清Caは5.5mEq/l, Pは1.3mEq/lで%TRPは72%であつた.末梢血の副甲状腺ホルモン(c-assay)は0.1ng/mlであつたが最下甲状腺静脈血では4.25ng/mlで原発性副甲状腺機能亢進症と診断した.気縦隔法で,縦隔内腺腫が疑われた.胸骨上窩部切開により縦隔内副甲状腺腺腫を摘出した.本例においてはX線検査で骨病変は認められず,血清Caの上昇も軽度で,本症例の原発性副甲状腺機能亢進症は尿路結石群と考えられる.欧米では原発性副甲状腺機能尤進症に膵炎を合併した症例の報告はかなり見られるが本邦では現在まで8例の報告があるにすぎず,胸水を伴つた膵炎を合併した原発性副甲状腺機能亢進症としては本報告が第1例である.

Endotoxin-induced acute lung injury in guinea pigs.

SDZ MRL 953 (SDZ), a novel immunostimulatory lipid A analog, has been reported to have immunopharmacological activities similar to those of lipopolysaccharide (LPS) but to have little of the toxicity of LPS. We investigated the effects of pretreatment with SDZ on Escherichia coli endotoxin-induced acute lung injury in guinea pigs. Four experimental groups consisted of saline control (n = 16), SDZ (-12 h) plus LPS (2 mg/kg of SDZ per kg of body weight injected intravenously 12 h before intravenous injection of 2 mg of LPS per kg; n = 15), SDZ (-10 min) plus LPS (SDZ injected 10 min before LPS injection; n = 10), and LPS alone (n = 16). The animals were sacrificed, and lung tissue was sampled 4 h after LPS or saline infusion. Lung injury was assessed by measuring the wet weight-to-dry weight ratio and the level of 125I-labeled albumin accumulation in bronchoalveolar lavage fluid relative to that in plasma. In the SDZ (-12 h) plus LPS group, these two parameters of acute lung injury were decreased compared with those in the LPS alone group. However, they were not decreased in the SDZ (-10 min) plus LPS group. We conclude that SDZ attenuates endotoxin-induced acute lung injury when it is administered 12 h before LPS injection. The attenuating effects of SDZ are speculated to be due to down regulation of the response to endotoxin rather than to receptor blocking.