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Nitric oxide and carbon monoxide diffusing capacities (D LNO and D LCO ) obey Fick's First Law of Diffusion and the basic principles of chemical kinetic theory. NO gas transfer is dominated by membrane diffusion (D M ), whereas CO transfer is limited by diffusion plus chemical reaction within the red cell. Marie Krogh, who pioneered the single-breath measurement of D LCO 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/D L ) was the sum of the membrane resistance (1/D M ) 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, D M for CO and Vc can be solved with simultaneous NO and CO inhalation. At near maximum exercise, D MCO 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 θ NO " recalculation reduced D MCO to 53% and increased Vc to 95% of morphometric values. © 2020 American Physiological Society. Compr Physiol 10:73-97, 2020., (Copyright © 2019 American Physiological Society. All rights reserved.)

The porcine model has contributed significantly to biomedical research over many decades. The similar size and anatomy of pig and human organs make this model particularly beneficial for translational research in areas such as medical device development, therapeutics and xenotransplantation. In recent years, a major limitation with the porcine model was overcome with the successful generation of gene-targeted pigs and the publication of the pig genome. As a result, the role of this model is likely to become even more important. For the respiratory medicine field, the similarities between pig and human lungs give the porcine model particular potential for advancing translational medicine. An increasing number of lung conditions are being studied and modeled in the pig. Genetically modified porcine models of cystic fibrosis have been generated that, unlike mouse models, develop lung disease similar to human cystic fibrosis. However, the scientific literature relating specifically to porcine lung anatomy and airway histology is limited and is largely restricted to veterinary literature and textbooks. Furthermore, methods for in vivo lung procedures in the pig are rarely described. The aims of this review are to collate the disparate literature on porcine lung anatomy, histology, and microbiology; to provide a comparison with the human lung; and to describe appropriate bronchoscopy procedures for the pig lungs to aid clinical researchers working in the area of translational respiratory medicine using the porcine model.

In asthma, airway smooth muscle (ASM) chemokine (C-X-C motif) receptor 3 (CXCR3) ligand production may attract mast cells or T lymphocytes to the ASM, where they can modulate ASM functions. In ASM cells (ASMCs) from people with or without asthma, we aimed to investigate JAK-STAT1, JNK, and Ca²⁺ involvement in chemokine (C-X-C motif) ligand (CXCL)10 and CXCL11 production stimulated by interferon-γ, IL-1β, and TNF-α combined (cytomix). Confluent, growth-arrested ASMC were treated with inhibitors for pan-JAK (pyridone-6), JAK2 (AG-490), JNK (SP-600125), or the sarco(endo)plasmic reticulum Ca²⁺ATPase (SERCA) pump (thapsigargin), Ca²⁺ chelator (BAPTA-AM), or vehicle before and during cytomix stimulation for up to 24 h. Signaling protein activation as well as CXCL10/CXCL11 mRNA and protein production were examined using immunoblot analysis, real-time PCR, and ELISA, respectively. Cytomix-induced STAT1 activation was lower and CXCR3 ligand mRNA production was more sensitive to pyridone-6 and AG-490 in asthmatic than nonasthmatic ASMCs, but CXCL10/CXCL11 release was inhibited by the same proportion. Neither agent caused additional inhibition of release when used in combination with the JNK inhibitor SP-600125. Conversely, p65 NF-κB activation was higher in asthmatic than nonasthmatic ASMCs. BAPTA-AM abolished early CXCL10/CXCL11 mRNA production, whereas thapsigargin reduced it in asthmatic cells and inhibited CXCL10/CXCL11 release by both ASMC types. Despite these inhibitory effects, neither Ca²⁺ agent affected early activation of STAT1, JNK, or p65 NF-κB. In conclusion, intracellular Ca²⁺ regulated CXCL10/CXCL11 production but not early activation of the signaling molecules involved. In asthma, reduced ASM STAT1-JNK activation, increased NF-κB activation, and altered Ca²⁺ handling may contribute to rapid CXCR3 ligand production and enhanced inflammatory cell recruitment.

Background: Activated mast cells are present within airway smooth muscle (ASM) bundles in eosinophilic asthma. ASM production of the chemokine CXCL10 plays a role in their recruitment. Thus the effects of glucocorticoids (fluticasone, budesonide), long-acting β2-agonists (salmeterol, formoterol) and thiazolidinediones (ciglitazone, rosiglitazone) on CXCL10 production by ASM cells (ASMC) from people with and without asthma were investigated in vitro., Methods: Confluent serum-deprived cells were treated with the agents before and during cytokine stimulation for 0-24 h. CXCL10 protein/mRNA, IκB-α levels and p65 activity were measured using ELISA, RT PCR, immunoblotting and p65 activity assays respectively. Data were analysed using ANOVA followed by Fisher's post-hoc test., Results: Fluticasone and/or salmeterol at 1 and 100 nM inhibited CXCL10 release induced by IL-1β and TNF-α, but not IFNγ or all three cytokines (cytomix). The latter was also not affected by budesonide and formoterol. In asthmatic ASMC low salmeterol, but not formoterol, concentrations increased cytomix-induced CXCL10 release and at 0.01 nM enhanced NF-κB activity. Salmeterol 0.1 nM together with fluticasone 0.1 and 10 nM still increased CXCL10 release. The thiazolidinediones ciglitazone and rosiglitazone (at 25 and 100 μM) inhibited cytomix-induced CXCL10 release but these inhibitory effects were not prevented by the PPAR-g antagonist GW9662. Ciglitazone did not affect early NF-κB activity and CXCL10 mRNA production., Conclusions: Thus the thiazolidinediones inhibited asthmatic ASMC CXCL10 release under conditions when common asthma therapies were ineffective or enhanced it. They may provide an alternative strategy to reduce mast cell-ASM interactions and restore normal airway physiology in asthma.

In asthma, airway smooth muscle (ASM) chemokine secretion can induce mast cell recruitment into the airways. The functions of the mast cell chemoattractant CXCL10, and other chemokines, are regulated by binding to heparan sulphates such as syndecan-4. This study is the first demonstration that airway smooth muscle cells (ASMC) from people with and without asthma express and shed syndecan-4 under basal conditions. Syndecan-4 shedding was enhanced by stimulation for 24 h with the Th1 cytokines interleukin-1β (IL-1β) or tumor necrosis factor-α (TNF-α), but not interferon-γ (IFNγ), nor the Th2 cytokines IL-4 and IL-13. ASMC stimulation with IL-1β, TNF-α, and IFNγ (cytomix) induced the highest level of syndecan-4 shedding. Nonasthmatic and asthmatic ASM cell-associated syndecan-4 protein expression was also increased by TNF-α or cytomix at 4-8 h, with the highest levels detected in cytomix-stimulated asthmatic cells. Cell-associated syndecan-4 levels were decreased by 24 h, whereas shedding remained elevated at 24 h, consistent with newly synthesized syndecan-4 being shed. Inhibition of ASMC matrix metalloproteinase-2 did not prevent syndecan-4 shedding, whereas inhibition of ERK MAPK activation reduced shedding from cytomix-stimulated ASMC. Although ERK inhibition had no effect on syndecan-4 mRNA levels stimulated by cytomix, it did cause an increase in cell-associated syndecan-4 levels, consistent with the shedding being inhibited. In conclusion, ASMC produce and shed syndecan-4 and although this is increased by the Th1 cytokines, the MAPK ERK only regulates shedding. ASMC syndecan-4 production during Th1 inflammatory conditions may regulate chemokine activity and mast cell recruitment to the ASM in asthma.

Background: Activated mast cell densities are increased on the airway smooth muscle in asthma where they may modulate muscle functions and thus contribute to airway inflammation, remodelling and airflow obstruction., Objectives: To determine the effects of human lung mast cells on the secretory and proliferative functions of airway smooth muscle cells from donors with and without asthma., Methods: Freshly isolated human lung mast cells were stimulated with IgE/anti-IgE. Culture supernatants were collected after 2 and 24 h and the mast cells lysed. The supernatants/lysates were added to serum-deprived, subconfluent airway smooth muscle cells for up to 48 h. Released chemokines and extracellular matrix were measured by ELISA, proliferation was quantified by [(3) H]-thymidine incorporation and cell counting, and intracellular signalling by phospho-arrays., Results: Mast cell 2-h supernatants reduced CCL11 and increased CXCL8 and fibronectin production from both asthmatic and nonasthmatic muscle cells. Leupeptin reversed these effects. Mast cell 24-h supernatants and lysates reduced CCL11 release from both muscle cell types but increased CXCL8 release by nonasthmatic cells. The 24-h supernatants also reduced asthmatic, but not nonasthmatic, muscle cell DNA synthesis and asthmatic cell numbers over 5 days through inhibiting extracellular signal-regulated kinase (ERK) and phosphatidylinositol (PI3)-kinase pathways. However, prostaglandins, thromboxanes, IL-4 and IL-13 were not involved in reducing the proliferation., Conclusions: Mast cell proteases and newly synthesized products differentially modulated the secretory and proliferative functions of airway smooth muscle cells from donors with and without asthma. Thus, mast cells may modulate their own recruitment and airway smooth muscle functions locally in asthma., (© 2011 John Wiley & Sons A/S.)

Increased levels of IL-6 are documented in asthma, but its contribution to the pathology is unknown. Asthma is characterized by airway wall thickening due to increased extracellular matrix deposition, inflammation, angiogenesis, and airway smooth muscle (ASM) mass. IL-6 binds to a specific membrane-bound receptor, IL-6 receptor-alpha (mIL-6Ralpha), and subsequently to the signaling protein gp130. Alternatively, IL-6 can bind to soluble IL-6 recpetor-alpha (sIL-6Ralpha) to stimulate membrane receptor-deficient cells, a process called trans-signaling. We discovered that primary human ASM cells do not express mIL-6Ralpha and, therefore, investigated the effect of IL-6 trans-signaling on the pro-remodeling phenotype of ASM. ASM required sIL-6Ralpha to activate signal transducer and activator 3, with no differences observed between cells from asthmatic subjects compared with controls. Further analysis revealed that IL-6 alone or with sIL-6Ralpha did not induce release of matrix-stimulating factors (including connective tissue growth factor, fibronectin, or integrins) and had no effect on mast cell adhesion to ASM or ASM proliferation. However, in the presence of sIL-6Ralpha, IL-6 increased eotaxin and VEGF release and may thereby contribute to local inflammation and vessel expansion in airway walls of asthmatic subjects. As levels of sIL-6Ralpha are increased in asthma, this demonstration of IL-6 trans-signaling in ASM has relevance to the development of airway remodeling.

Inflammation and vascular leakage are prevalent in asthma. This study aimed to elucidate the mechanisms involved in serum potentiation of cytokine-induced granulocyte macrophage colony stimulating factor (GM-CSF) production by human airway smooth muscle cells and to identify possible factors responsible. Serum-deprived cells at low density were stimulated with TNF-alpha and IL-1beta for 24 h. Human AB serum (10%), inhibitors of RNA and protein synthesis or specific signaling molecules, or known smooth muscle mitogens were then added for 24 h. Culture supernatants were analyzed for GM-CSF levels, and cells were harvested to assess viability, cell cycle progression, GM-CSF-specific mRNA content, and p38 phosphorylation. Serum potentiated GM-CSF release when added before, together with (maximal), or after the cytokines. The potentiation involved both new GM-CSF-specific mRNA production and protein synthesis. The mitogens IGF, PDGF, and thrombin all potentiated GM-CSF release, and neutralizing antibodies for EGF, IGF, and PDGF reduced the serum potentiation. Inhibitor studies ruled as unlikely the involvement of p70(S6kinase) and the MAPK p42/p44, two signaling pathways implicated in proliferation, and the involvement of the MAPK JNK, while establishing roles for p38 MAPK and NF-kappaB in the potentiation of GM-CSF release. Detection of significant p38 phosphorylation in response to serum stimulation, through Western blotting, further demonstrated the involvement of p38. These studies have provided evidence to support p38 being targeted to interrupt the cycle of inflammation, vascular leakage and cytokine production in asthma.

The transfer factor, Tl,co (with the transfer coefficient, Kco, also known as the transfer factor per unit alveolar volume, [Tl/Va]), is one of the most useful clinical tests of pulmonary function, the only one which specifically focuses on pulmonary microcirculation. It was originally devised in 1909 as a physiological tool to assess the diffusive capacity of the lung as a gas exchanger. It was subsequently developed as a clinical tool, but cumbersome analytical techniques delayed its introduction into clinical medicine until 1950s. The physiology of the carbon monoxide transfer factor (also called the diffusing capacity Dl,co) is based on the Roughton-Forster equation which partitions Dl,co, a conductance, into membrane (Dm) and red cell (thetaVc) diffusion conductances. Recent work (1987-2001) suggests that 70-80% of the resistance to CO (and O2) diffusion may reside in the red cell fraction. The clinical implication is that Tl,co and Kco are 'windows' onto the pulmonary microcirculation. As regards reference values for clinical use, Tl,co depends on age, height and gender. Kco, which is actually a rate constant, is independent of gender, and is affected principally by age. A schema is presented for the clinical interpretation of Tl,co. As Tl,co is derived from the product of Kco and the accessible alveolar volume (Va), examination of these two components (Kco and Va) will usually suggest a specific pathophysiological mechanism as the explanation for a reduction in Tl,co.

Eosinophils are present throughout the airway wall of asthmatics. The nature of the interaction between human airway smooth muscle cells (ASMC) and eosinophils was investigated in this study. We demonstrated, using light microscopy, that freshly isolated eosinophils from healthy donors rapidly attach to ASMC in vitro. Numbers of attached eosinophils were highest at 2 h, falling to 50% of maximum by 20 h. Eosinophil attachment at 2 h was reduced to 72% of control by anti-VCAM-1, and to 74% at 20 h by anti-ICAM-1. Pre-treatment of ASMC for 24h with TNF-alpha, 10 nM, significantly increased eosinophil adhesion to 149 and 157% of control after 2 and 20 h. These results provide evidence that eosinophil interactions with ASMC involve VCAM-1 and ICAM-1 and are modulated by TNF-alpha.

The aim of the study was to measure the peripheral blood levels of soluble E-selectin in patients with systemic inflammation and compare them with in vivo granulocyte activation, pulmonary intravascular granulocyte pooling, pulmonary extravascular granulocyte migration and 99mTc-diethylenetriaminepenta-acetic acid (DTPA) aerosol clearance, an index of lung injury. The level of soluble E-selectin was measured by capture ELISA. Granulocytes were labelled with 111In and 99mTc for quantification of pulmonary granulocyte kinetics. The pulmonary vascular granulocyte pool (PGP) was expressed as a fraction of the total blood granulocyte pool. Pulmonary granulocyte migration was quantified on 24-h images using the 111In signal. Granulocyte activation was quantified as the percentage of circulating cells showing shape change ('primed'). Lung injury was assessed from the clearance rate of inhaled 99mTc-DTPA aerosol. Eighteen patients with systemic inflammation were studied: five with inflammatory bowel disease, eight with systemic vasculitis, four with graft versus host disease and one with a recent renal transplant. The peripheral blood levels of soluble E-selectin were significantly elevated in patients with systemic inflammation. The level of soluble E-selectin showed a significant association with granulocyte migration (Spearman rank correlation coefficient, Rs=0.53; P<0.05) but not with PGP or with the percentage of cells showing shape change (P>0.05 for both). Granulocyte migration was bimodal: patients were therefore subdivided into 'migrators' and 'non-migrators'. Soluble E-selectin level, 99mTc-DTPA clearance and PGP, but not the percentage of cells showing shape change, were significantly higher in migrators than in non-migrators. We conclude that pulmonary intravascular granulocyte pooling is increased in the presence of increased numbers of circulating primed granulocytes but increased pooling does not by itself promote granulocyte migration into the lung interstitium. Insofar as an elevated level of E-selectin in peripheral blood reflects vascular endothelial activation, the data are consistent with the notion that pulmonary endothelial activation is required, in addition to granulocyte activation and an expanded PGP, for granulocyte migration into lung parenchyma and, therefore, for lung injury to occur.

Study Objectives: To assess the effectiveness of pulse oximetry and radioisotope measurement of right-to-left (R-L) shunt for the early detection of pulmonary arteriovenous malformations (PAVMs) in patients with hereditary hemorrhagic telangiectasia (HHT)., Design: Patients with HHT had serial measurements of the following: (1) arterial oxygen saturation (SaO2) by pulse oximetry in erect and supine positions, and on maximal exercise using cycle ergometry; (2) quantitative radioisotope measurements of R-L shunt using IV 99mTc-labeled macroaggregates of albumin; and (3) routine pulmonary function. After percutaneous transcatheter embolization of all PAVMs with feeding vessel diameters > 3 mm, residual PAVMs were assessed with selective digital subtraction pulmonary angiography. Using postembolization angiography as the "gold standard," SaO2 and radioisotope shunt measurements after embolization were analyzed retrospectively using logistic regression to assess the ability of each test to predict for the presence of residual PAVMs., Results: Of the 66 patients included, 40 had small PAVMs remaining postembolization. Using univariate logistic regression, radioisotope shunt and erect saturation showed a significant relationship with the presence of residual PAVMs (p=0.001, 0.005, respectively). Erect SaO2 < or = 96% had 73% sensitivity and 35% specificity for detecting PAVMs. Radioisotope shunt >3.5% of cardiac output had 87% sensitivity and 61% specificity for detecting PAVMs., Conclusions: These results confirm that noninvasive measurements are useful in the screening of patients with HHT for the presence of PAVMs without need for angiography and its associated risks, and that radionuclide scanning is better than pulse oximetry.

The increase in the amount of airway smooth muscle in the bronchial wall associated with asthma is partly due to hyperplasia. It is therefore important to determine which factors regulate growth and especially proliferation. In this study, we describe the effect of interleukin-4 (IL-4), a mast cell- and T lymphocyte-derived cytokine, on human airway smooth muscle proliferation as determined by [3H]thymidine uptake in the presence of fetal bovine serum (FBS), platelet-derived growth factor, basic fibroblast growth factor, and thrombin. IL-4 (5, 15, 50, and 150 ng/ml) significantly decreased 10% FBS-induced proliferation by 50, 73, 43, and 46%, respectively. The proliferative responses to platelet-derived growth factor (20 and 40 ng/ml), basic fibroblast growth factor (30 ng/ml), and thrombin (1 and 10 U/ml) were significantly reduced by 19, 21, 37, 36, and 57% respectively in the presence of 50 ng/ml of IL-4. We investigated the effect of IL-4 and other known inhibitors of smooth muscle proliferation, namely PGE2, heparin, and forskolin, on intracellular cAMP concentrations. IL-4 (50 ng/ml) and heparin (100 U/ml) did not alter intracellular cAMP levels when cells were treated with 1 or 10% FBS. PGE2 (1 microM) and forskolin (10 microM) significantly increased cAMP concentration above the control value in nonproliferating cells (1% FBS treated) by 7- and 37-fold, respectively. The effect of IL-4 (50 ng/ml), PGE2 (1 microM), and forskolin (10 microM) on cyclin D1 protein expression in 10% FBS-stimulated human airway smooth muscle cells was also examined. PGE2 and forskolin did not significantly inhibit cyclin D1 expression. However, IL-4 decreased cyclin D1 expression by 21%. These results provide evidence that IL-4 decreases human airway smooth muscle cell proliferation via a mechanism that is cAMP independent and mediated, in part, by a decrease in cyclin D1 protein expression.

There is limited and conflicting evidence regarding the exposure-response relationship between exposure to crystalline silica and silicosis; the level of risk to current workers remains uncertain. We conducted an epidemiologic investigation of 1,809 workers in the diatomaceous earth industry, where exposures to crystalline silica are primarily to the cristobalite form. On the basis of the median of three independent readings, 81 (4.5%) workers were judged to have opacities on chest radiographs (small opacities, profusion >= 1/0, and/or large opacities). Age-adjusted relative risk of opacities increased significantly with cumulative exposure to crystalline silica. The concentration of respirable crystalline silica to which workers were exposed (highly correlated with period of hire) was an important determinant of risk after accounting for cumulative exposure. For workers with an average exposure to crystalline silica of <= 0.50 mg/m3 (or hired >= 1950), the cumulative risk of opacities for a cumulative exposure to crystalline silica of 2.0 mg/m3-yr was approximately 1.1%; for an average exposure > 0.50 mg/m3 (or hired < 1950), the corresponding cumulative risk was 3.7%. These findings indicate an exposure-response relationship between cumulative exposure to crystalline silica and radiographic opacities; moreover, the relationship was substantially steeper among workers exposed at the highest average concentrations of crystalline silica.

Background/aims: Severe hypoxaemia in patients with chronic liver disease in the absence of intrinsic lung disease, the hepatopulmonary syndrome, is associated with pulmonary vascular dilatation and may be an indication for liver transplantation. Divergence between two methods of measuring right to left shunt (radiolabelled albumin macroaggregates and 100% oxygen breathing) has been described, but the mechanism and reason for the inter-patient variability for this shunt difference are not well understood., Methods: Eight hepatopulmonary syndrome patients were studied, with characteristic pulmonary diffusion abnormalities (carbon monoxide transfer factor 41+/-5 (mean+/-SE)% predicted) and significant decreases in arterial oxygen saturation (%) on standing vs. supine (-10%+/-3) and on exercise vs. rest (-15%+/-2). All had hypoxaemia at rest (arterial oxygen tension 8.2+/-0.6 kPa), partially corrected by breathing 100% oxygen (48.2+/-8.8 kPa). Pulmonary angiography was performed and right to left shunt measured by two independent methods: (a) 100% oxygen breathing and (b) i.v. injection of radiolabelled microspheres., Results: Measurement of right to left shunt with 99mTc-labelled albumin macroaggregates confirmed significant intrapulmonary microvascular dilatation, i.e. an "anatomical" shunt equalling 32+/-4% of cardiac output. Shunt measurements made simultaneously by the classical 100% oxygen technique were significantly smaller (19+/-3%, p=0.01). For individuals, the difference between the 99mTc-albumin macroaggregate shunt and the 100% oxygen shunt ranged from 2% to 30% absolute, convergence suggesting larger shunt channels (pure anatomical shunt) and divergence representing a combination of anatomical shunt and alveolar-capillary diffusion limitation (smaller microvascular channels)., Conclusions: Hypoxaemia in the hepatopulmonary syndrome may be due functionally either to right to left shunting or to diffusion limitation, depending upon the degree of dilatation of the pulmonary microvessels.

Measurement of the clearance rate of inhaled aerosols of 99mTc-diethylenetriamine pentaacetic acid (DTPA) from distal airway to pulmonary capillary is a sensitive technique for the detection of lung injury. As the solute diffuses across the blood-gas barrier, the concentration in circulating blood increases, giving rise to a background signal superimposed on the signal from residual DTPA in the airway. Background subtraction is conventionally based on the thigh, but this tissue has the disadvantage in that its composition, in terms of the relative volumes of its extracellular extravascular and intravascular compartments (a ratio of approximately 4:1), is quite different from that of the lung (<1:6). With comparison to the thigh, we examined alternative regions for background, liver, and cranium, which have extravascular-to-intravascular compartment ratios much closer to these for the lung, to determine the most appropriate background for correction of the pulmonary signal. From 1 min after intravenous injection of 99mTc-DTPA, the time-activity curves recorded by a gamma camera over the liver and lung in a group of otherwise normal cigarette smokers decreased up to 30 min after injection, with time courses that could essentially be superimposed on each other; the curve recorded over the thigh with a separate scintillation probe continued to increase. The curve recorded over the cranium had a time course similar to that for the liver and lung. Following aerosol inhalation, the lung clearance rates over the initial 7 min when background subtraction was used, based on the liver, cranium, and thigh were, respectively, 4.9 +/- 2.9, 4.7 +/- 2. 6, and 5.4 +/- 3.4 (SD) %/min, compared with 4.1 +/- 2.2%/min without subtraction. The corresponding values based on 30 min of data were 3.3 +/- 1.4, 3.4 +/- 1.4, 4.2 +/- 2.3, and 2.8 +/- 1. 0%/min. When the liver was used for background, the lung clearance curves were clearly multiexponential, whereas thigh correction tended to give curves that were monoexponential or even convex upward on semilogarithmic axes. With an appropriate region for background, the true shape of a lung curve can be identified, which permits the study of an intervention on the clearance while it is in progress. The intravenous DTPA, required for calibrating the background regions, can be given before inhalation of the tracer.

Background: Tachyphylaxis to the cardiac effects of beta-adrenoceptor stimulation after long-term beta2-agonist administration is well recognized, but the influence on global cardiac beta-adrenoceptor density has not been previously investigated in vivo. Positron emission tomography (PET) has made possible the noninvasive quantification of regional receptor density. This study assesses the effect of long-term beta2-agonist dosing on cardiac beta-adrenoceptors., Methods and Results: Beta-adrenoceptors in the hearts of 29 healthy male subjects aged 35 +/- 8 years were imaged and quantified in vivo by means of PET and compared with the receptor density in the same subjects' lung tissue. Mononuclear leukocyte (MNL) beta-receptor density was determined in vitro by means of a radioligand binding assay. Beta-receptor density was 8.41 +/- 2.03 pmol/gm tissue in heart, 10.81 +/- 1.91 pmol/gm tissue in lung, and 38.0 +/- 17.5 fmol/mg protein on MNLs. There was a weak relationship between cardiac and pulmonary beta-receptor densities (r = 0.45, p < 0.02) but not between cardiac and MNL receptor density. In seven subjects, the measurements were repeated after 2 weeks of albuterol treatment (4 mg orally twice daily and 200 microg inhaled four times daily in the first week, with doubling of the dose during the second week). After the albuterol treatment, beta-receptor density fell on average by 19% (p < 0.05) in the heart compared with 22% (p < 0.05) in the lung and 42% (p < 0.05) in MNLs. Correlations were found between the percentage changes in receptor density in heart and lung (r = 0.98, p < 0.001) and in heart and MNLs (r = 0.99, p < 0.002)., Conclusions: Two weeks of high-dose albuterol results in equivalent downregulation of beta-receptors in vivo, both in the lung and in the heart.

To examine whether there is a primary deficit in beta-adrenoceptor density in asthma, pulmonary and cardiac beta-receptor density was determined in vivo with positron emission tomography (PET) in 10 male asthmatic subjects (36 +/- 8 yr of age) and compared with that in 30 age-matched normal male subjects (36 +/- 8 yr of age). Pulmonary beta-receptor density was 10.3 +/- 1.8 pmol/g tissue for the asthmatic group and 10.9 +/- 1.9 for the normal group. Cardiac beta-receptor density was 9.1 +/- 3.3 pmol/g for the asthmatic group and 8.8 +/- 2.3 pmol/g for the normal group. There was no difference in either pulmonary or cardiac beta-receptor density between the two groups. In addition, an inverse relationship was observed between FEV1 % predicted and pulmonary beta-receptor density in asthmatic subjects. In conclusion, beta-receptor numbers are normal in untreated asthmatic subjects.

In human subjects, chronic beta2-agonist dosing reduces mononuclear leukocyte (MNL) beta-adrenoceptor numbers. The aim of this study was to investigate whether this downregulation also occurs in the lung. Seven healthy male subjects were treated for 2 wk with oral (up to 16 mg/d) and inhaled (up to 1.6 mg/d) albuterol (salbutamol in Europe). Pulmonary maximal beta-adrenoceptor binding capacity (Bmax) was determined in vivo using positron emission tomography (PET) and the beta-receptor antagonist ligand, 11C-labeled CGP-12177, before and after the 2-wk chronic dosing. MNL Bmax was also measured, using a radioligand binding assay and 3H-labeled CGP-12177. Bronchodilator responses to the beta2-agonist were determined after each PET scan by measuring the change in specific airway conductance (SGaw) after increasing doses of inhaled albuterol. Pulmonary and MNL Bmax fell by 22% +/- 14% (p < 0.05) and 42% +/- 19% (p < 0.05) respectively. The changes in pulmonary and MNL Bmax were correlated (r = 0.9, p < 0.05). There was also a reduction in the bronchodilator response to inhaled albuterol. In a further six subjects, pulmonary and MNL Bmax did not change during an acute infusion of albuterol (2 to 4 microg/kg/h). The reduction in pulmonary beta-adrenoceptor numbers after chronic albuterol dosing may be predictable from the changes observed in circulating MNL cells.

1. The aim of the study was to examine the relationship between granulocyte activation, pulmonary intravascular granulocyte transit, pulmonary extravascular granulocyte migration and lung injury in patients with systemic conditions (bone marrow transplant recipients, inflammatory bowel disease and systemic vasculitis) in which abnormalities of pulmonary granulocyte traffic have previously been reported. 2. A double 111In-99mTc granulocyte labelling technique was used for quantification of granulocyte kinetics in 23 patients, of whom five were control patients. The pulmonary vascular granulocyte pool was measured from dynamic data centred on the 99mTc signal and expressed as a percentage of the total blood granulocyte pool. Granulocyte migration was quantified on 24 h images using the 111In signal. Granulocyte activation was measured as the percentage of cells showing a change in shape. The clearance rate of an inhaled aerosol of 99mTc-diethylenetriaminepenta-acetic acid (DTPA) was used as a marker of lung injury. 3. Pulmonary granulocyte pool, migration, activation and aerosol clearance, although highly variable in the patient groups, were, in general, elevated compared with the controls. 4. Granulocyte activation correlated with pulmonary granulocyte pool (Rs = 0.72, n = 22, P < 0.01), while the t1/2 of DTPA clearance correlated with migration (Rs = -0.84, n = 17, P < 0.01). Fifteen patients had an expanded pulmonary granulocyte pool, of whom six with no evidence of migration, had a normal DTPA clearance, while nine, who had an abnormal migration signal, had an accelerated DTPA clearance. The pulmonary granulocyte pool in these nine was significantly higher than in the six without a migration signal. 5. Activation of granulocytes results in delayed transit through the lung vasculature. With increasing margination, granulocytes migrate into the lung interstitium and injure the lung. An increased intravascular pool does not by itself lead to lung injury.

Unlabelled: A new method has recently been developed to quantify pulmonary beta-adrenergic receptors in vivo using PET. This study used in vitro radioligand binding assay (RLBA) as the gold standard to validate in vivo PET measurements., Methods: Five male patients with lung cancer aged 57 yr (range 42-67 yr) were studied. PET scanning was performed the day before thoracotomy to determine regional pulmonary beta-receptor density. RLBA was carried out on cell membranes prepared from specimens of lung tissue obtained at the thoracotomy to measure beta-receptor density in vitro. In both cases, the hydrophilic nonselective beta-antagonist radioligand (S)-CGP-12177 was used. For PET studies, this was labeled with 11C and for RLBA with 3H., Results: In the PET study, beta-receptor density (Bmax) was 9.43 +/- 1.32 pmole g-1 tissue. In the RLBA study, Bmax was 99.0 +/- 15.5 fmole mg-1 protein, equivalent to 9.90 +/- 1.55 pmole mg-1 tissue. These values are in good agreement with previously reported in vitro measurements on human lung membranes using 125I-iodocyanopindolol. A correlation was found between beta-adrenergic density obtained using PET and beta-adrenergic density obtained using RLBA (r = 0.92; p < 0.05)., Conclusion: The results support the use of PET as a new method for imaging and the way for studies of physiological and pharmacological regulation of beta-adrenergic receptors through noninvasive serial measurements.

Background: Reduced beta adrenergic receptor density in tumours has been reported in previous in vitro studies. The aim of the present study was to assess whether this occurs in vivo., Methods: Pulmonary beta adrenoceptors were imaged and quantified in vivo using positron emission tomography (PET) and the beta antagonist radioligand (S)-[11C]CGP-12177 in five men with lung tumours of mean age 58 years (range 42-68). The histology of the tumours was squamous cell carcinoma in two cases, adenocarcinoma in one, carcinoid tumour in one, and large cell carcinoma in one. The regional blood volume and extravascular tissue density were also measured using PET. Regions of interest were drawn for both non-tumour and tumour lung tissue., Results: The mean (SD) blood volume was 0.142 (0.025) ml/ml in tumour regions and 0.108 (0.010) ml/ml in normal lung regions--a difference of 31%. Mean (SD) extravascular tissue density was 0.653 (0.133) g/ml in tumour regions, substantially higher than in normal lung regions (0.157 (0.021) g/ml). On the contrary, beta receptor density was 5.1 (1.8) pmol/g in tumour regions, lower than the value of 9.9 (1.6) pmol/g found in adjacent normal lung--a difference of 48%., Conclusions: In vivo beta adrenoceptor density is reduced in human lung tumours.

Platelet-activating factor (PAF) is a short-acting, lipid-soluble autocoid, inhalation of which causes an immediate pulmonary vascular sequestration of granulocytes and a peripheral neutropenia. We investigated the effect of PAF inhalation on the pulmonary clearance rate of inhaled 99mTc-DTPA in order to test the hypothesis that the pulmonary sequestration of granulocytes results in acute lung injury. In nine normal nonsmoking adults, the rate of clearance of DTPA, corrected for background activity, was 1.5 (SD 0.7) %/min over the first 10 min after inhalation. Inhalation of 4.8 micrograms PAF abruptly increased the clearance rate to a mean value of 2.3 (1.4) %/min (p < 0.05). No increase in clearance was observed in four nonsmoking subjects who inhaled vehicle only. The mean overall increase after PAF was 87% of the baseline clearance, significantly different (p < 0.05) from the corresponding change in the control group, which was -17%. After PAF, the clearance rate returned to baseline values within 10 min in all subjects. In all subjects who inhaled PAF, but in none who inhaled vehicle, there was an immediate neutropenia of 51 (SD 25) % of the baseline value (p < 0.01). This neutropenia persisted longer than the corresponding accelerated DTPA clearance and was still 74 (36) % of the baseline value at 10 min. Furthermore, there was no correlation between the increase in DTPA clearance induced by PAF inhalation and the decrease in peripheral blood granulocyte count. We conclude that PAF inhalation results in an increase in pulmonary DTPA clearance, probably not mediated by pulmonary vascular granulocyte sequestration.

We have developed a technique for measuring the pulmonary granulocyte pool (PGP) as a fraction of the whole body total blood granulocyte pool (TBGP). The technique "captures" a dose of 99mTc-labeled granulocytes in a region of interest (ROI) over the lung during first pass by integrating an input time-activity curve from an ROI over the pulmonary artery, superior vena cava, or right ventricle. The ratio of the estimated first-pass count rate and the count rate in the same lung ROI after equilibration of the cells between the circulating and pulmonary pools (15-30 min) represents the PGP/TBGP. The technique was validated in eight subjects by using 99mTc-labeled macroaggregated human serum albumin. With corrections for background and injected doses, the ratios of first-pass granulocyte-to-macroaggregated human serum albumin count rates given by the three input ROIs were close to unity [superior vena cava 0.98 +/- 0.079 (SD), right ventricle 1.01 +/- 0.070, and pulmonary artery 0.97 +/- 0.073]. Significant increases in PGP/TBGP were demonstrated in systemic inflammation. Thus, in patients with inflammatory bowel disease, it was 0.22 +/- 0.07 (n = 7) compared with 0.08 +/- 0.01 (n = 5) in control subjects. It was also elevated in patients with systemic vasculitis (0.34 +/- 0.07; n = 5), in transplant recipients (0.33 +/- 0.08; n = 5), and in patients with osteomyelitis (0.15 +/- 0.06; n = 4). We conclude that this is a valid technique for quantifying the PGP that is expanded in several conditions associated with systemic inflammation.

Although tumour necrosis factor alpha (TNF alpha) may be involved in the pathology of asthma, little is known about its role in mediator release from inflammatory cells in human lung. We investigated whether TNF alpha induced histamine release from mast cells in human chopped lung tissue and whether it modulated antigen-induced release of histamine and leukotrienes C4/D4/E4 from passively sensitized lung tissue. Spontaneous histamine release in the presence of 1 nM TNF alpha for up to 4 h at 37 degrees C was not significantly different from spontaneous histamine release alone (6.1 +/- 1.3% and 6.1 +/- 1.5% of total tissue histamine at 4h respectively; n = 3). Lung tissue was passively sensitized to the house dust mite Dermatophagoides pteronyssinus by incubating it in serum from an atopic volunteer donor for 3 h at 37 degrees C. Treatment of the sensitized lung tissue with 1 nM TNF alpha for 60 min prior to challenge with a low concentration (1.8 AU) of D. pteronyssinus caused a significant increase in the amount of histamine release induced by the antigen from 0.2 +/- 0.6% to 1.9 +/- 1.0% of total tissue histamine (P = 0.045, n = 6). The release of leukotriene C4/D4/E4 induced by the same concentration of antigen was not significantly changed by the TNF alpha treatment (39.5 +/- 9.1 and 55.6 +/- 17.7 pg/100 microliters supernatant sample respectively; n = 6). These results suggest that TNF alpha may be involved in potentiation of histamine release in allergic asthma, particularly in the presence of low antigen concentrations.

A case of metastatic carcinoid syndrome with hypoxaemia is described. The hypoxaemia appeared to be due to intrapulmonary shunting. There was improvement in resting and exercise arterial oxygen saturations following chemotherapy with streptozotocin and 5-fluorouracil. This was followed by a decrease in the tumour bulk which may have led to a reduction in the secretion of the vasodilator products responsible for shunting. Some features of this case suggest that the hypoxaemia might have been due to dilatation of precapillary and capillary vessels of the pulmonary micro-circulation. These features are part of the so-called 'hepatopulmonary syndrome', of which this case appears to represent a less severe form.

Regional pulmonary glucose metabolism (MRglu; mumol h-1 g-1), extravascular lung density (D(EV); g cm-3) and vascular volume (VB; ml cm-3) were measured in a single midthoracic transaxial slice (approximately 2 cm thick) using position emission tomography (PET) in seven patients with histologically proven sarcoidosis. The measurements were repeated 1-7 months later after steroid therapy (in two cases, no treatment) in order to assess MRglu as an index of inflammation and relate it to routine pulmonary function tests, chest radiography and serum angiotensin converting enzyme (SACE) levels. MRglu was computed from serial lung scans and peripheral venous blood samples for 60 min following an i.v. injection of 18F-2-fluoro-2-deoxy-D-glucose (18FDG). Both MRglu (which was increased in six of seven patients) and elevated SACE levels returned to normal in those patients treated with high-dose steroids. Regional vascular volume was normal in six of seven cases and did not change significantly with therapy. The high tissue density measured in all patients decreased significantly in two of three patients treated with 40 mg prednisolone daily. The abnormal MRglu observed in active sarcoidosis becomes normal pari passu with SACE levels during high-dose steroid therapy. We conclude that MRglu measured with 18FDG and PET may reflect "disease activity" in sarcoidosis in quantitative terms (per gram lung tissue) and in respect of disease distribution.

Background: Patients with arteriovenous malformations are routinely monitored with arterial oxygen saturation (SaO2) estimations (breathing air) from which an oxygen shunt fraction can be calculated. This simple estimation has been compared with an anatomically defined estimate of the right to left shunt using a radioisotopic method. The fall in SaO2 which occurs in patients with pulmonary arteriovenous malformations in the erect posture and at high lung volumes was used to test the ability of SaO2 alone to follow changes in right to left shunt., Methods: Radiolabelled albumin macroaggregates (99mTc-MAA) or microspheres (MS) were injected intravenously and kidneys and lungs were imaged. The shunt fraction (QS/QTTc) in the supine position at functional residual capacity (baseline) was obtained by quantifying right kidney radioactivity. On standing or while breath holding at total lung capacity, shunt fraction was calculated from baseline QS/QTTc and from lung counts and the injected dose. Arterial oxygen saturation (SaO2) was recorded by a pulse oximeter for calculation of the oxygen shunt (QS/QTO2) (breathing air)., Results: In the postural study (n = 8) SaO2 decreased from a mean (SD) value of 89 (5)% supine to 80 (6)% erect, corresponding to QS/QTO2 28 (8)% and 44 (8)% respectively. QS/QTTc increased from 28.7 (10.3)% to 39 (14.3)%. In the lung volume study (n = 8) QS/QTTc increased from 16.6 (11.5)% at functional residual capacity to 23.3 (11.9)% at total lung capacity while QS/QTO2 increased from 19.5 (7.5)% to 25.9 (10.6)% respectively. When all measurements were compared for QS/QTTc% and QS/QTO2% (n = 32) the difference in the mean values was 2.5% (absolute) and the limits of agreement between the two methods were +38% to -18% (relative). In neither the postural nor the volume study did delta (QS/QTO2) reliably predict delta (QS/QTTc)%., Conclusions: In pulmonary arteriovenous malformations the simple physiological shunt calculated from SaO2 breathing air agreed well with the anatomical right to left shunt measured with 99mTc-MAA, but predicted poorly the changes in anatomical shunt induced by postural or lung volume changes.

This study describes a method for quantifying the pulmonary trapping of indium-111 labelled polymorphonuclear (PMN) cells in patients with inflammatory bowel disease (IBD) in comparison to non-inflamed controls. Twenty patients with extensive IBD were studied by 111In-PMN scintigraphy. Gamma-camera images were obtained at 2.5-4 h (early) and 20-25 h (late) after the injection of autologous PMNs labelled in plasma with 111In-tropolonate. Local uptake in the chest, iliac bone marrow, spleen and liver was quantified as the counts per pixel per second per MBq of injected 111In for both early and late scans. Fourteen subjects without inflammatory disease were studied as controls. IBD patients showed significantly greater loss of splenic activity between early and late scans compared with controls (mean +/- SD: -35.7% +/- 16.6% versus -4.5% +/- 6.1%, P < 0.001). There was no significant difference between control and IBD groups with respect to liver and bone marrow uptake on both early and late scans. Chest uptake was significantly higher in patients with IBD on both early (6.4 +/- 1.6 cps/MBq/pix) and late (5.6 +/- 1.5 cps/MBq/pix) scans, compared with the controls (4.8 +/- 1.3 cps/MBq/pix, P < 0.005 and 3.4 +/- 1.0 cps/MBq/pix, P < 0.001 respectively). The chest uptake in the control group on the late scans demonstrated a significant linear correlation with iliac uptake (y = 0.23x + 0.41, r = 0.87, n = 14). Assuming in controls that there is no parenchymal uptake of 111In, this regression enables an estimate to be made, based on iliac counts, of the count rate from bone marrow in the chest wall.(ABSTRACT TRUNCATED AT 250 WORDS)

The in vivo regional distribution of pulmonary beta-adrenoceptors was imaged and quantified in humans with the hydrophilic beta-adrenoceptor antagonist (S)-CGP-12177 labeled with carbon-11 [(S)-[11C]CGP-12177] and positron emission tomography (PET). Six normal male volunteers and eight patients with hypertrophic cardiomyopathy were studied. PET scanning consisted of transmission (tissue density), C15O (blood volume), and (S)-[11C]CGP-12177 (beta-adrenoceptor) emission scans. High-specific-activity (S)-[11C]-CGP-12177 (7.1 +/- 2.0 micrograms, 6.5 +/- 2.1 GBq/mumol) was given intravenously followed by a low-specific-activity (S)-[11C]CGP-12177 injection (34.0 +/- 4.8 micrograms, 2.3 +/- 0.8 GBq/mumol). Binding capacity (Bmax) was calculated in each region of interest as picomoles per gram by normalizing it to the local extravascular tissue density. In normal subjects, average Bmax for all regions of interest was 14.8 +/- 1.6 (SD) pmol/g, which is similar to previously reported in vitro values. In both groups there were no differences in beta-adrenoceptor density between peripheral and central regions nor between right and left lungs. In patients with hypertrophic cardiomyopathy, extravascular tissue density was 24% higher than in normal subjects; Bmax per milliliter thoracic volume was correspondingly higher but was not different from that in normal subjects when expressed per gram tissue (15.8 +/- 2.6 pmol/g). These data suggest that in vivo beta-adrenoceptor density may be quantifiable in humans with the use of PET. This should offer a means to study physiological regulation through repeat measurements.

A survey of workers in seven man made mineral fibre (MMMF) production plants, the subject of a previous report, was conducted, with other blue collar workers serving as regional comparisons. Based on the median reading of chest radiographs by five readers, a low prevalence of small opacities, all at the 1/0 and 1/1 profusion levels, was again found: for workers with MMMFs, 23/1435 (1.6%); for comparison workers, 2/305 (0.7%). Spirometric measurements indicated generally healthy populations, and were not related to presence of opacities. Ninety three per cent (21/23) of MMMF workers with opacities worked at the two plants with the highest exposures to fine fibres, resulting in a dose-response relation across plants. For one location, the prevalences of opacities for the MMMF and comparison workers were not significantly different (5.9% (13/220) v 3.1% (2/65)). No comparison x ray films were obtained for the MMMF plant with the highest prevalence (6.6%), so a second phase of the study was conducted, with pre-employment films from these two plants. On this second reading, the prevalence of opacities was lower; there were no significant differences between the two groups of films, and no relation between opacities and exposure indices. There was considerable inter and intrareader variability. These results indicate no adverse clinical, functional or radiographic signs of effects of exposure to MMMFs in these workers.

The majority of patients with intrapulmonary right-to-left shunting due to pulmonary arteriovenous malformations-exhibit good maximum exercise capacity (> 70% predicted) despite profound arterial oxygen desaturation. We studied seven such patients to assess tissue oxygen delivery during steady-state exercise. From rest to exercise [50 +/- 7 (SE) W] arterial saturation fell from 80 +/- 3 to 74 +/- 3%, and mean right-to-left shunt increased slightly from 31 +/- 4 to 34 +/- 5% (P = NS). Minute ventilation was high for oxygen uptake, and the ventilatory equivalent was raised (174 +/- 19% predicted) and was correlated with shunt size (r = 0.93). The majority of the patients maintained pulmonary alveolar blood flow within the predicted range for their power output, but total cardiac output was increased to 142 +/- 11% predicted due to flow through the shunt. Consequently, on exercise, oxygen delivery per unit oxygen consumption [2.3-3.3 (normal range 1.6-2.4)] and calculated mixed venous oxygen tension (27.0 +/- 0.8 Torr) were preserved. Arterial PCO2 rose on exercise by 2.8 +/- 1.2 Torr, in proportion to the ratio of flow through the shunt to total cardiac output (r = 0.73), but remained low (33.1 +/- 1.4 Torr) in absolute terms. The high cardiac output on exercise may be facilitated by a low pulmonary vascular resistance (0.33 +/- 0.08 mmHg.1-1.min, measured at rest), which may explain why exercise performance is better in these patients than in patients with equivalent hypoxemia from other causes.

We have investigated the role of endothelium-derived relaxing factor in modulating hypoxic pulmonary vasoconstriction by inhibiting its synthesis with the false substrate NG-monomethyl-L-arginine (L-NMMA) in the isolated blood-perfused lungs of Wistar rats after chronic hypoxia (CH, fractional inspiratory O2 concentration 10%) for 15 h, 2 days, and 7 days. Lungs were perfused with blood of normal hematocrit at constant flow (18 ml/min) ventilated with 1) 95% air-5% CO2 (normoxia) and 2) 2% O2-5% CO2-93% N2 (hypoxia) and were studied in the absence and presence of L-NMMA (30 and 300 microM) or L-arginine (L-Arg, 1 and 6 mM) in separate groups. Pulmonary arterial pressure (Ppa) rose incrementally with hypoxic exposure (all P < 0.05 vs. normoxic control group). Hypoxic pulmonary vasoconstriction (HPV) was markedly reduced after 15 h and 2 days of CH: the mean increases in Ppa (delta Ppa) in hypoxia were 15.3, 3.5, 3.8, and 13.6 mmHg in control rats and rats exposed to 15 h (P < 0.05 vs. control and 7 days of CH), 2 days (P < 0.001 vs. control and 7 days of CH), and 7 days of CH, respectively. Ppa in control rats and rats exposed to 15 h, 2 days, and 7 days of CH were 137, 179, 184, and 166% of control, respectively, after 30 microM L-NMMA (all P < 0.05 when expressed as percent change vs. no L-NMMA). Similar augmentation in HPV was seen after 30 microM L-NMMA, with all hypoxic groups having a greater response than control groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Background: Positron emission tomography, performed with isotopes of very short half life, can be used to relate local lung tissue density to local ventilation and to the ventilation:perfusion ratio. This method has been used in 10 patients with severe chronic airflow obstruction and differing values for carbon monoxide transfer factor (TLCO) and transfer coefficient (KCO)., Methods: Ventilation (VA) and the ventilation:perfusion ratio (V/Q), lung density, and blood volume were measured regionally in a single transaxial section at mid-heart level with the patients in a supine position. Alveolar volume, extravascular tissue lung density, and perfusion (Q) were derived. Twenty five regions with abnormalities in the ventilation images were analysed., Results: Tissue density showed a negative correlation with the ratio V/Q (r = 0.55) and a positive correlation with Q (r = 0.59) and blood volume (r = 0.65). In four patients with a low carbon monoxide transfer factor (TLCO) and transfer coefficient (KCO) < 50% predicted many regions with low VA had low tissue density and normal or high V/Q. On the other hand, in four patients with TLCO and KCO > 50% predicted many regions with low VA had normal or high tissue density and low values of V/Q. The other two patients had patterns between these two extremes. Individual ratios between mean values of tissue density and V/Q had a positive correlation with KCO (% pred; r = 0.79)., Conclusions: These findings link structural differences with distinctive functional patterns; they reinforce the view that bronchial inflammation or oedema predominate in some patients with chronic airflow obstruction, whereas alveolar destruction is the major feature in others.

Pulmonary function and disease activity were assessed in a large series of patients with acromegaly (19 men and 16 women). Large lungs, defined as a vital capacity greater than 120 per cent of predicted normal occurred in six of 19 males and six of 16 females. Ten of the 12 patients with elevated vital capacity had active disease (growth hormone greater than 5 mU/l during a glucose tolerance test). There was no association with duration of disease. Diffusing capacity was normal overall but DLCO greater than 120 per cent occurred in six of 14 females and one of 18 males. Significant intrathoracic airflow obstruction occurred in eight of 35 patients, six of whom were nonsmokers. Upper (extrathoracic) airflow obstruction was the most common pulmonary function abnormality. A maximal expiratory/inspiratory flow ratio greater than 1.0 at 50 per cent vital capacity occurred in 13 of 18 males and four of 16 female patients, and there was an association with disease activity (17 of 25 subjects with active disease had upper airflow obstruction compared to one of nine in remission; p = 0.01). Nocturnal hypoxaemia occurred in three of 13 patients studied: six of this group had upper airways obstruction. They were all male with elevated growth hormone levels and upper airflow obstruction. In summary, in 35 acromegalics (26 with active disease), large lungs occurred in 12 patients (34 per cent) and upper airflow obstruction in 17 patients (50 per cent). The latter may develop nocturnal hypoxaemia--this was seen in three of six patients with upper airflow obstruction. Upper airways obstruction was more common in males (13 of 18 compared to four of 16 females; p = 0.04) and its presence in males should arouse suspicion of nocturnal hypoxaemia.

To determine the effect of the heart on regional ventilation, Krypton-81m (81mKr) tomographic (SPECT) ventilation scans were recorded in seven patients with cardiomegaly and four normal subjects in the supine and prone positions. All patients had a cardiothoracic ratio of greater than 0.50 and clear lung fields radiographically. Using standard gamma camera tomographic reconstruction techniques, images of transaxial slices were obtained during a 360 degree rotation around the thorax of the subject breathing the radioactive gas 81mKr. The transaxial images, acquired over 10 min were aligned in each posture at the level of the cardiac apex, mid-heart, and aortic arch and were matched in relation to a radioactive marker on the chest wall and to anatomic landmarks. A horizontal line (gravity independent and parallel to the couch) was drawn on the transaxial section through the dorsal regions of the right and left lung. Counts per resolution element (12 to 15 mm) were plotted along this line and the ratios of the peak values in right and left lung compared. These ratios represent differences in regional ventilation per unit lung volume. In controls the mean left-to-right (L/R) peak count ratio varied from 0.91 to 1.00 at the three levels (range: 0.76 to 1.04); there were no significant differences between supine and prone. In patients with cardiomegaly the mean (+/- SEM) L/R peak count ratio at cardiac apex, mid-heart, and aortic arch was 0.46 (+/- 0.08), 0.55 (+/- 0.07), and 0.89 (+/- 0.08) when supine and 1.04 (+/- 0.07), 1.05 (+/- 0.05), and 1.08 (+/- 0.07) when prone, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Single photon emission computed tomography, a rotating gamma camera, and continuous inhalation or infusion of krypton 81m (half life 13 seconds) were used to measure regional ventilation (V), perfusion (Q), and ventilation-perfusion (V/Q) ratios in five normal subjects in supine, prone, and lateral decubitus postures and in three asthmatic patients (supine posture only) before and after inhalation of 2.5 mg nebulised salbutamol. Vertical and horizontal gradients of V, Q, and V/Q were examined at three levels in each lung in regions of 1.9 cm3 size. In normal subjects V and Q increased along the axis of gravity in all postures and at all levels in the lung except for V in the prone position. Smaller horizontal gradients were found with an increase in V and Q from caudal to cranial--again except in the prone posture, where the gradient was slightly reversed. Constraint to outward motion of the ventral chest and abdominal wall is the most likely explanation for the different behaviour in the prone posture. In chronic asthma the vertical gradients of V and V/Q were the reverse of normal, but the Q gradient was normal. Bronchodilator treatment did not affect the vertical or horizontal gradients significantly, but analysis of individual regions showed that, relatively, V/Q worsened in 42% of them; this was associated in two thirds with an increase in fractional Q. After inhalation of beta agonist local vasodilatation may influence V/Q ratios in some units more than bronchodilatation.

1. The distribution of regional function in the lungs of six patient with bilateral diaphragmatic paralysis was investigated by continuous inhalation and infusion of the radioactive gases 81mKr and 85mKr during tidal breathing. 2. In the supine and right lateral decubitus postures the vertical distribution of ventilation per unit alveolar volume was less in the dependent zones, the reverse of that found in normal subjects. In the upright posture ventilation was slightly decreased at the lung base. Perfusion per unit alveolar volume was more uniformly distributed than normally in the upright posture, and decreased from superior to inferior in the supine posture. In the lateral decubitus posture, perfusion of the lower lung was greater than that of the upper. Ventilation/perfusion ratios were more uniformly distributed in the patients than in normal subjects, except in the right lateral decubitus posture. 3. Alterations in the distribution of ventilation may be explained in terms of the altered mechanical interaction of chest wall, mediastinal and abdominal contents, with selective use of intercostal and accessory muscles. The effects on the distribution of blood flow are probably related to the low end-expiratory lung volume.

Using a specially designed mask and steady-state administration of the short-lived radioactive gas 81mKr, we measured the distribution of the ventilation-perfusion ratio (VA/Q) in the lungs of normal conscious standing greyhound dogs during tidal breathing. This model allows measurement of regional lung function unaffected by anesthesia and mechanical ventilation. An assessment of the distribution of VA/Q in the lungs of normal greyhound dogs revealed that topographically, ventilation and blood flow are well matched in the conscious dog.

The distributions per unit volume of extravascular water (EVLW), blood volume, and blood flow were measured in isolated perfused vertical dog lungs. A steady-state tracer technique was employed using oxygen-15, carbon-11, and nitrogen-13 isotopes and external scintillation counting of the 511-KeV annihilation radiation common to all three radionuclides. EVLW, and blood volume and flow increased from apex to base in all preparations, but the gradient of increasing flow exceeded that for blood and EVLW volumes. The regional distributions of EVLW and blood volume were almost identical. With increasing edema, lower-zone EVLW increased slightly relative to that in the upper zone. There was no change in the distribution of blood volume or flow until gross edema (100% wt gain) occurred when lower zone values were reduced. In four lungs the distribution of EVLW was compared with wet-to-dry ratios from lung biopsies taken immediately afterwards. Whereas the isotopically measured EVLW increased from apex to base, the wet-to-dry weight ratios remained essentially uniform. We concluded that isotopic methods measure only an "exchangeable" water pool whose volume is dependent on regional blood flow and capillary recruitment. Second, the isolated perfused lung can accommodate up to 60% wt gain without much change in the regional distribution of EVLW, volume, or flow.

Regional ventilation per unit alveolar volume (V/VA) and regional lung expansion (FRCR/TLCR) were measured in twelve normal male human subjects in seated, supine, lateral decubitus and prone postures using a gamma camera and inhalation of the radioactive gases 81Krm (half-life 13 sec) and 85Krm (half-life 4.4 h). FRCR/TLCR decreased from superior to inferior in all postures except prone where it was uniform; V/VA increased from superior to inferior except in the prone position where it was uniform. In the horizontal axis FRCR/TLCR and V/VA were uniformly distributed except for cranial to caudal gradients (with lower values caudally) in supine and lateral decubitus postures. In the prone posture V/VA tended to be higher in caudal lung zones.

The inhibitory effects of fenoterol, a beta 2-adrenoceptor agonist, on the release of SRS-A leukotrienes and histamine from chopped human lung tissue were measured and selective beta-adrenoceptor antagonists used to investigate the nature of the receptors involved. Fenoterol 0.01-1.0 microM inhibited the antigen-induced release of SRS-A and histamine, but not the release induced by the calcium ionophore A23187. Propranolol 0.1 and 1.0 microM and butoxamine 10 and 100 microM significantly antagonized the effects of fenoterol 0.1 microM on SRS-A and histamine at concentrations which affect (beta 2-adrenoceptors, while atenolol 0.1 to 10 microM showed no antagonism at concentrations which affect beta 1-adrenoceptors. These results suggest that adrenoceptors in human lung which modulate the immunological release of SRS-A leukotrienes are of the beta 2-subtype as for histamine release.

A 99Tcm aerosol of particle size 0.12 micron and the gas 81Krm were administered to four normal subjects and to eleven patients with airway disease. Posterior-anterior gamma camera images of erect lungs were compared qualitatively and quantitatively, and 99Tcm clearance rates were measured. Qualitatively the two images were similar in normal subjects but differed in most patients owing to small regions of high count density in the 99Tcm images. In a few patients, regional variations in ventilation were defined more finely by the aerosol. In both groups a significant vertical gradient in 99Tcm count density relative to 81Krm count density was found. Penetration of 99Tcm to the lung periphery relative to the hilar region was similar to that of 81Krm in the normal subjects and less than that of 81Krm in the patients. Possible causes of the differing distributions are discussed. The images obtained with the aerosol in the two groups studied were similar to those reported for larger particle aerosols.

Positive end-expiratory pressure (PEEP) is widely used in the treatment of severe pulmonary oedema, although its effects on the clearance of water and small solutes from alveolus to blood are not well characterized. We studied the effect of the application of 10 cmH2O of PEEP on the flux of inhaled 99mTc-diethylene-triamine-penta-acetic acid (DTPA) from lung to blood in six healthy smoking and six nonsmoking subjects. The rate of flux was corrected for possible changes in pulmonary blood volume during PEEP by use of an intravenous injection of 99mTc-DTPA. The baseline clearance rate (K, % X min-1) for nonsmokers was 1.48 +/- 0.12 (mean +/- SE) and increased to 2.40 +/- 0.29 during PEEP (p less than 0.05). In contrast, the mean clearance rate for smokers was 3.26 +/- 0.82 at baseline and 3.03 +/- 0.82 during PEEP (p = NS). The application of positive end-expiratory pressure appears to increase alveolar solute flux in nonsmokers but not in smokers, suggesting that the pathway for solute clearance in smokers is governed by different rate-limiting steps to those of nonsmokers.