Peripheral blood mononuclear cell response to YKL-40 and Galectin-3 in cystic fibrosis.

BACKGROUND: Elevated circulating levels of YKL-40 correlate with disease severity in Cystic Fibrosis (CF), but the role of YKL-40 in the inflammatory response in CF is still under investigation. Our main goal was to evaluate if YKL-40 can modulate the expression of major cytokines (IL-6, IL-10, IL-13) implicated in the inflammatory response in CF. A secondary goal was to explore the interactions between YKL-40 and other circulating proteins to determine the impacts on cytokine modulation. METHOD: Peripheral blood mononuclear cells (PBMCs) were isolated from the blood of 83 adult CF patients in stable clinical condition. PBMCs were treated with human YKL-40 followed by the measure of IL-6, IL-10 and IL-13 gene expression. Protein arrays were used to explore the interactions between YKL-40 and circulating proteins. Interaction with Galectin-3 (GAL3) was identified, and confirmed by binding assay. Cytokine gene expressions were again monitored by RT-qPCR after PBMC treatment with GAL3, with or without YKL-40 co-stimulation. RESULTS: Following YKL-40 stimulation, PBMC gene expression of IL-6, IL-10 and IL-13 varies across patients. IL-6 and IL-13 are coexpressed, but this response was different in male and female patients. GAL3 protein was detected in the blood of CF patients, and a molecular interaction with YKL-40 was identified. GAL3 did not interfere with the YKL-40 stimulation of IL-6, IL-10 and IL-13 but may modulate the coexpression. CONCLUSION: We observed that YKL-40 stimulation had a variable impact on IL-6, IL-10, and IL-13 gene expression in CF PBMCs and uncovered an interaction between GAL3 and YKL-40 in the serum of CF patients. Our findings suggest that YKL-40 is not only a biomarker of disease severity in CF, but it might play an active role in the inflammatory pathophysiology of the disease.

No relationship between mean plasma glucose and glycated haemoglobin in patients with cystic fibrosis-related diabetes.

AIM: Cystic fibrosis-related diabetes (CFRD) prevalence has increased dramatically with the improved life expectancy of patients with cystic fibrosis (CF). Glycated haemoglobin (HbA(1c)) is an important tool for monitoring blood glucose control but, unlike in type 1 and type 2 diabetes, a correlation between HbA(1c), fructosamine and mean plasma glucose has not been clearly established in CF. This study aimed to examine the relationship between mean plasma glucose and HbA(1c) or fructosamine in stable patients with CFRD. METHODS: Fifteen type 1 diabetes and 13 CFRD patients (HbA(1c)<9.0%; no anaemia), matched for age and body mass index (BMI), provided 72 capillary blood glucose profiles taken 3days/month for three months. At the end of this time, HbA(1c) and fructosamine were measured. Mean plasma glucose was estimated using the Diabetes Control and Complications Trial (DCCT) conversion formula, and linear regressions carried out to establish its relationship with HbA(1c) and fructosamine. RESULTS: In type 1 diabetes patients, mean plasma glucose correlated significantly with HbA(1c) (r=0.68; P=0.005). In CFRD patients, no correlation was found between mean plasma glucose and HbA(1c) (r=0.24; P=0.460). Also, no association was found between mean plasma glucose, representing the month before blood sampling, and fructosamine in either group. CONCLUSION: Unlike in type 1 diabetes, HbA(1c) did not correlate with mean plasma glucose in CFRD subjects. Thus, having a normal HbA(1c) may not be sufficient to indicate a low risk of diabetes complications in CFRD. Further studies are required to explain such a discrepancy.

Beta-adrenergic agonists increase lung liquid clearance in anesthetized sheep.

We did experiments to determine whether beta-adrenergic agonists increase lung liquid clearance in anesthetized ventilated adult sheep and, if so, whether the increase is mediated by beta receptors and what mechanism is involved. We instilled 100 ml of autologous serum either alone or with a beta-adrenergic agonist (terbutaline, 10(-5) M, or epinephrine, 5.5 X 10(-6) M) into one lower lobe. After 4 h both terbutaline and epinephrine increased lung liquid clearance. The increase in lung liquid clearance was inhibited when propranolol (a beta blocker) or amiloride (a sodium channel blocker) was added to the terbutaline. Increased clearance was not explained by changes in pulmonary hemodynamics, pulmonary blood flow, or lung lymph flow. We conclude that beta-adrenergic agonists increase lung liquid clearance in anesthetized intact adult sheep. This increase is mediated through beta receptors and probably depends on increased active transport of sodium across the alveolar barrier.

Normal adiponectin levels despite abnormal glucose tolerance (or diabetes) and inflammation in adult patients with cystic fibrosis.

RATIONALE: Circulating adiponectin levels are negatively associated with glucose intolerance, inflammation and central adiposity. Since these conditions are common in cystic fibrosis (CF), we examined whether adiponectin values are altered in these patients. AIM: To determine if CF patients have altered adiponectin levels and if these levels correlate with glucose tolerance categories (normal, impaired glucose tolerance (IGT) and cystic fibrosis-related diabetes (CFRD)), insulin resistance or inflammatory markers such as fibrinogen and C-reactive protein (CRP). METHODS: Oral glucose tolerance tests (OGTTs) were performed and adiponectin levels were measured in 90 CF patients not known to be diabetic and 15 healthy controls matched for age, sex and body mass index (BMI). Inflammatory markers, serum albumin concentrations and the clinical status of CF patients (i.e. pulmonary function) were also examined. RESULTS: CF pathology was characterized by a high prevalence (43.5%) of glucose tolerance abnormalities: 26.5% of IGT and 17.0% of newly diagnosed CFRD. CF patients also presented systemic inflammation as revealed by a significant increase of fibrinogen (P=0.029) in all patients and higher CRP levels in CFRD patients compared to the controls (P<0.05). On the other hand, CF and control subjects had similar albumin serum concentration. While CF patients and controls had similar serum adiponectin values, women had significantly higher hormone levels than men (P<0.001). Adiponectin levels did not correlate with glucose tolerance, inflammatory markers or insulin resistance. On the other hand, they correlated positively with both total and HDL-cholesterol (P<0.001). CONCLUSION: CF patients did not show any alterations in adiponectin levels despite insulin resistance, glucose intolerance and sub clinical chronic inflammation. Thus, CF appears to be one of the rare conditions in which discordance between adiponectin values and insulin resistance or inflammation is evident.

Association between glucose intolerance and bacterial colonisation in an adult population with cystic fibrosis, emergence of Stenotrophomonas maltophilia.

BACKGROUND: Diabetes is common in cystic fibrosis (CF). Glucose can be detected in the airway when the blood glucose is elevated, which favours bacterial growth. We investigated the relationship between dysglycemia and lung pathogens in CF. METHODS: Cross-sectional and prospective analysis of CF patients (N=260) who underwent a 2h-oral glucose tolerance test. Clinical data was collected. RESULTS: Stenotrophomonas maltophilia (S. maltophilia) was the sole bacteria increased in dysglycemic (AGT: 20.2%, CFRD: 21.6%) patients compared to normotolerants (NGT: 8.7%). S. maltophilia positive patients with dysglycemia had more pulmonary exacerbation events compared to NGTs (1.22 vs 0.63, P=0.003). The interaction between S. maltophilia colonisation and glucose tolerance status significantly increases the risk of lower lung function (P=0.003). Its growth was not affected by the evolution of the glucose tolerance after three years follow-up. CONCLUSION: Prevalence of S. maltophilia was higher in dysglycemic patients, supporting the idea that S. maltophilia is a marker of disease severity in CF.

Ralstonia mannitolilytica in cystic fibrosis: A new predictor of worse outcomes.

BACKGROUND: Patients with Cystic Fibrosis are subject to repeated respiratory tract infections, with recent increasing isolation of unusual pathogens. Ralstonia species have lately been isolated at our institution, an organism historically frequently misidentified as Burkholderia or Pseudomonas. The prevalence of Ralstonia spp. in cystic fibrosis populations has yet to be determined, along with its clinical implications. CASE PRESENTATIONS: Seven patients out of the 301 followed at our cystic fibrosis clinic have had Ralstonia strains identified in their respiratory tract. Most strains identified were multi-drug resistant. After aquisition of Ralstonia spp., the patients' clinical course was characterized by more frequent and more severe respiratory infections along with prolonged hospitalizations, greater decline of lung function, and greater mortality. The mortality rate in this group of patients was 86%. No other factor that could explain such a dramatic evolution was identified upon review of patient data. Some of the strains involved were recognized as clones on Pulse Field Electrophoresis Gel, raising the question of person-to-person transmission. CONCLUSION: New pathogens are identified with the evolution of the microbiota in cystic fibrosis respiratory tracts. In our cohort of patients, acquisition of Ralstonia spp. was associated with dramatic outcomes in terms of disease acceleration and raised mortality rates. It is of critical importance to continue to better define the prevalence and clinical impact of Ralstonia in cystic fibrosis populations.

Diabetes: a major co-morbidity of cystic fibrosis.

Cystic fibrosis-related diabetes (CFRD) is a frequent complication of cystic fibrosis, its prevalence increases with age of patient and is close to 30% at the age of 30 years. As life expectancy greatly increases, the number of cystic fibrosis patients developing diabetes will increase too. CFRD shares some features with type 1 and type 2 diabetes, initial phase is characterised by postprandial hyperglycaemia followed by a progression toward insulin deficiency. Insulin deficiency is an essential factor in the development of diabetes with an additional contribution of insulin resistance. Systematic screening with an oral glucose tolerance test is recommended from the age of 14 years because clinical signs of CFRD are often confused with signs of pulmonary infection and CFRD occurrence is associated with weight and pulmonary function deterioration. In observational studies CFRD diagnosis is associated with a significant increase in mortality, while treatment allow correction of weight and lung deterioration suggesting that CFRD has a significant impact on CF evolution. Microvascular complications are recognised, although paucity of data does not permit a clear description of their natural history. Annual screening for microvascular complication is recommended. There is no evidence by now that CF patients develop macrovascular complications. The only recommended pharmacological treatment is insulin therapy.

Airway function in lifetime-nonsmoking older asbestos workers.

Previous studies of lung function in asbestos workers have documented airflow limitation in many of the workers, but the specific influence of asbestos exposure could not be clearly differentiated from the effects of the cigarette smoking habit. In this study, airway function was evaluated in lifetime-nonsmoking, long-term workers of the mines and mills of Québec. The 17 asbestos workers in this study had worked for an average of 28 years in the mines and mills of the local asbestos industry and did not have any other respiratory industrial dust exposure. They did not have a history of previous pulmonary disease and did not meet the usual diagnostic criteria for chronic bronchitis, emphysema, or asthma. Seven of the workers met the diagnostic criteria for asbestosis and 10 workers did not. The latter group of workers did not differ from a matched control group except in terms of a higher isoflow volume (p less than 0.05). The workers with asbestosis, however, had a restrictive pattern of lung function, increased isoflow volume, and increased upstream resistance at low lung volumes (p less than 0.01). Lung biopsy in three of the patients with the disease demonstrated peribronchiolar alveolitis and fibrosis with obliteration and narrowing of the small airways. These data on lifetime-nonsmoking, long-term asbestos workers provide further evidence of small airway obstruction associated with asbestos exposure and independent of the smoking habit. This airflow limitation was observed predominantly in workers with a restrictive pattern of lung function associated with peribronchiolar alveolitis. The lifetime-nonsmoking asbestos workers without restrictive patterns of lung function had minimal dysfunction of the peripheral airways.

Maternal cigarette smoking and fetal oxygen transport: a study of P50, 2,3-diphosphoglycerate, total hemoglobin, hematocrit, and type F hemoglobin in fetal blood.

The current study was undertaken to determine whether the O2 carrying capacity of newborns born to mothers who smoke can accommodate to carbon monoxide poisoning to compensate for the potential tissue hypoxia induced by CO. From a cohort of 1,222 women and newborn infants the total hemogloblin concentration, hematocrit, and carboxyhemoglobin (HbCO) were measured and analyzed with regard to the maternal HbCO level and the number of cigarettes smoked per day. Also, for 100 pairs of mothers, of whom 50 were smokers and 50 nonsmokers, and their newborns, measurements were made of the intraerythrocyte concentration of 2,3-diphosphoglycerate (2,3-DPG), the hemoglobin concentration, and the affinity of hemoglobin for oxygen by determination of O2 tension for 50% of Hb-O2 saturation (P50). The results showed no significant relationship between smoking habits of mothers and their levels of hemoglobin, P50, and 2,3-DPG; only the hematocrit was slightly increased in smoking mothers. However, in fetal blood a significant correlation was found between the number of cigarettes smoked per day and levels of hemoglobin, hematocrit, and P50. The P50 decreased in relationship to the increase in maternal HbCO. The P50 change was brought about by an increase in hemoglobin F found in the fetuses of mothers who smoked. Although all these changes were statistically significant, these mechanisms of acclimatization to CO poisoning appeared trivial in magnitude. It is concluded that the human fetus does not have a biologic capacity to accommodate to maternal cigarette smoking, and therefore the fetus is particularly susceptible to the adverse effects of cigarette smoking.

Hydrochlorothiazide-associated pulmonary edema.

The findings in a patient who developed low-pressure pulmonary edema on two separate occasions immediately following the ingestion of a single triamterene-hydrochlorothiazide tablet (Dyazide) are presented. It is postulated that this was related to the hydrocholorothiazide component of the drug. Although 12 cases have been reported, the pathophysiology remains obscure. Mitogenic stimulation of the patient's lymphocytes to concanavalin A, phytohemagglutinin, and pokeweed mitogen was assessed. Blastogenic responses to Staphylococcus aureus antigen, triamterene, and hydrochlorothiazide were also assessed. No hypersensitivity response could be demonstrated to either triamterene or hydrochlorothiazide. The initially low white blood cell count, associated with hemoconcentration, increased in the first 24 h in the hospital. This observation is consistent with intrapulmonary sequestration of granulocytes causing pulmonary edema.

Treatment of ARDS.

Improved understanding of the pathogenesis of acute lung injury (ALI)/ARDS has led to important advances in the treatment of ALI/ARDS, particularly in the area of ventilator-associated lung injury. Standard supportive care for ALI/ARDS should now include a protective ventilatory strategy with low tidal volume ventilation by the protocol developed by the National Institutes of Health ARDS Network. Further refinements of the protocol for mechanical ventilation will occur as current and future clinical trials are completed. In addition, novel modes of mechanical ventilation are being studied and may augment standard therapy in the future. Although results of anti-inflammatory strategies have been disappointing in clinical trials, further trials are underway to test the efficacy of late corticosteroids and other approaches to modulation of inflammation in ALI/ARDS.

Effect of exogenous cAMP and aminophylline on alveolar and lung liquid clearance in anesthetized sheep.

A substantial body of evidence indicates that active transport of ions is important in modulating the resolution process of pulmonary edema. The biochemical regulation of this ion transport mechanism is still under investigation. In this study we evaluated the effect of an adenosine 3',5'-cyclic monophosphate (cAMP) analogue [dibutyryl cAMP (DBcAMP)] and a phosphodiesterase inhibitor (aminophylline) given alone or together on lung liquid and protein clearance. To study lung liquid and protein clearance, we measured the removal of 100 ml of autologous serum from the air spaces of anesthetized and ventilated adult sheep. Either serum alone or serum mixed with 10(-3) M DBcAMP, 10(-3) M or 10(-5) M aminophylline, or 10(-3) M aminophylline plus 10(-3) M DBcAMP was instilled. After 4 h, the residual lung water was 73.5 +/- 8.7 ml when serum alone was instilled and 56.8 +/- 13.6 ml when aminophylline and DBcAMP were given together. Neither aminophylline nor DBcAMP alone increased lung liquid clearance. However, the increase in clearance cannot be explained by an increase in protein clearance or changes in the pulmonary hemodynamics. These data suggest that the cAMP second messenger system can stimulate lung liquid clearance in vivo.

Long-term clearance of liquid and protein from the lungs of unanesthetized sheep.

We measured the removal of 100 ml of autologous serum from the air spaces and lungs of unanesthetized, spontaneously breathing sheep at 4, 12, and 24 h. In the first 4 h, there was a rapid clearance of the liquid volume (8.3%/h), similar to our results in anesthetized ventilated sheep (Matthay et al., J. Appl. Physiol. 53: 96-104, 1982). However, liquid removal progressively slowed to 3.3 and 1.4%/h at 12 and 24 h, respectively. In contrast, protein clearance (as measured by 125I-albumin instilled with the serum) was monoexponential and slow (1%/h). The slowing of liquid clearance appears to be a function of the rising protein osmotic pressure of the residual protein in the air spaces (protein concentration doubled in 24 h). Because protein solutions are chemotactic for neutrophils, we quantified the movement of liquid from the extracellular space into the alveolar compartment with a plasma protein tracer (131I-albumin), so that our final calculation of alveolar liquid clearance would take into account bidirectional movement of liquid across the alveolar barrier. The corrected values for net liquid clearance are slightly faster (less than 10% of the instilled volume).

Electrical impedance tomography can monitor dynamic hyperinflation in dogs.

We assessed in eight dogs the accuracy with which electrical impedance tomography (EIT) can monitor changes in lung volume by comparing the changes in mean lung conductivity obtained with EIT to changes in esophageal pressure (Pes) and to airway opening pressure (Pao) measured after airway occlusion. The average volume measurement errors were determined: 26 ml for EIT; 35 ml for Pao; and 54 ml for Pes. Subsequently, lung inflation due to applied positive end-expiratory pressure was measured by EIT (delta VEIT) and Pao (delta VPAO) under both inflation and deflation conditions. Whereas delta VPAO was equal under both conditions, delta VEIT was 28 ml greater during deflation than inflation, indicating that EIT is sensitive to lung volume history. The average inflation delta VEIT was 67.7 +/- 78 ml greater than delta VPAO, for an average volume increase of 418 ml. Lung inflation due to external expiratory resistance was measured during ventilation by EIT (delta VEIT,vent) and Pes (delta VPes,vent) and at occlusion by EIT (delta VEIT,occl), Pes, and Pao. The average differences between EIT estimates and delta VEIT,occl were 5.8 +/- 44 ml for delta VEIT,vent and 49.5 +/- 34 ml for delta VEIT,occl. The average volume increase for all dogs was 442.2 ml. These results show that EIT can provide usefully accurate estimates of changes in lung volume over an extended time period and that the technique has promise as a means of conveniently and noninvasively monitoring lung hyperinflation.

Monitoring changes in lung air and liquid volumes with electrical impedance tomography.

Electrical impedance tomography (EIT) uses electrical measurements at electrodes placed around the thorax to image changes in the conductivity distribution within the thorax. This technique is well suited to studying pulmonary function because the movement of air, blood, and extravascular fluid induces significant conductivity changes within the thorax. We conducted three experimental protocols in a total of 19 dogs to assess the accuracy with which EIT can quantify changes in the volumes of both gas and fluid in the lungs. In the first protocol, lung volume increments from 50 to 1,000 ml were applied with a large syringe. EIT measured these volume changes with an average error of 27 +/- 6 ml. In the second protocol, EIT measurements were made at end expiration and end inspiration during regular ventilation with tidal volume ranging from 100 to 1,000 ml. The average error in the EIT estimates of tidal volume was 90 +/- 43 ml. In the third protocol, lung liquid volume was measured by instilling 5% albumin solution into a lung lobe in increments ranging from 10 to 100 ml. EIT measured these volume changes with an average error of 10 +/- 10 ml and was also able to detect into which lobe the fluid had been instilled. These results indicate that EIT can noninvasively measure changes in the volumes of both gas and fluid in the lungs with clinically useful accuracy.

Alveolar epithelial fluid clearance persists in the presence of moderate left atrial hypertension in sheep.

The effect of moderate left atrial (LA) hypertension on alveolar liquid clearance (ALC) was investigated in anesthetized, ventilated sheep, surgically prepared to measure lung lymph flow as well as hemodynamics. To simulate alveolar edema, 3-4 ml/kg of isosmolar 5% albumin in Ringer lactate were instilled into each lower lobe, and ALC was measured. After 4 h of LA hypertension (24 cmH2O), ALC was similar to that in control sheep (31 +/- 3% with LA hypertension vs. 34 +/- 10% with normal LA pressure). Because plasma epinephrine levels were moderately elevated in the presence of LA hypertension, ALC was then studied in the presence of LA hypertension following bilateral adrenalectomy. Without endogenous release of epinephrine, ALC was significantly reduced compared with normal LA pressure (20 +/- 7% compared with 34 +/- 10%, P < 0.05). Thus endogenous catecholamines caused a submaximal stimulation of ALC in the presence of LA hypertension. Exogenous administration of aerosolized beta2-agonist therapy with salmeterol increased ALC in the presence of normal LA pressure but had no stimulatory effect in the presence of moderate LA hypertension. Therefore, we tested the hypothesis that endogenous release of atrial natriuretic factor (ANF) may downregulate alveolar epithelial Na+ and fluid transport in the presence of LA hypertension. There was a modest twofold increase in plasma ANF levels after LA hypertension. Additional in vitro studies demonstrated that, in the presence of beta2-agonist stimulation, ANF decreased Na+ pump activity (Na+-K+-ATPase) in isolated rat alveolar epithelial type II cells. ANF may downregulate vectorial Na+ and fluid transport stimulated by endogenous or exogenous beta-adrenergic agonist stimulation in the presence of LA hypertension. In summary, ALC continues even in the presence of moderate LA hypertension. Aerosolized beta2-adrenergic agonist therapy significantly increased ALC, but only when LA pressure was normal.

Protein clearance from the air spaces and lungs of unanesthetized sheep over 144 h.

We studied the rate, the routes, and the mechanisms for protein clearance from the air spaces and lungs of 20 unanesthetized sheep over 144 h. We instilled 100 ml of autologous serum labeled with 125I-albumin into one lung. At the end of 24, 48, 96, or 144 h, the lungs were removed and the residual native protein and 125I-albumin in the air spaces were determined by bronchoalveolar lavage. Also the fraction of the instilled 125I-albumin remaining in the rest of the lung was measured in the lung homogenate. Clearance of the 125I-albumin from the lung into the plasma, lymph, thyroid, urine, and feces was also determined. The removal of both the 125I-albumin and the native protein from the air spaces was slow, following a monoexponential decline. The removal rate of the 125I-albumin from the air spaces was slightly but significantly faster (1.6%/h) than the clearance rate of the native protein (0.9%/h). Clearance of the 125I-albumin from the lung also followed a slow monoexponential decline at a rate of 1.4%/h. At all time periods, 75% of the 125I-albumin remaining in the lung was located in the air spaces, thus indicating that the pulmonary epithelium is the principal barrier to protein clearance from the normal lung. Macrophages appeared to play a minor role in alveolar protein clearance because the quantity of 125I-albumin present in the phagocytic cells in the air spaces was less than 1% of the instilled 125I-albumin at all time periods. However, macrophages may play some role in protein clearance after 48 h because we visualized phagolysosomes in macrophages, and there was an increase in free iodine in lung lavage, urine, thyroid, and feces after 48 h. However, gel electrophoretic studies showed that most of the 125I-albumin was cleared from the lung as an intact molecule, although only 24.7 +/- 4.7% of the 125I-albumin was cleared by the lymphatics.

Alveolar liquid and protein clearance from normal dog lungs.

To determine whether liquid and protein clearance from the air spaces and lungs of anesthetized and unanesthetized dogs is the same as in sheep, we quantified these variables at three different time periods (4, 8, and 12 h) by instilling heparinized plasma (3 ml/kg) labeled with 125I-albumin into one lower lobe. Protein clearance, measured from the residual 125I-albumin in the lung homogenate, was slow and monoexponential (approximately 1%/h), similar to our previous data for protein clearance from the lungs in sheep. Lung liquid clearance in dogs, however, was 50% less than in previous experiments in sheep. Residual lung liquid (as percent of instilled) was 88.7 +/- 7.0 at 4 h, 70.5 +/- 9.1 at 8 h, and 64.0 +/- 5.8 at 12 h. At each time period, alveolar protein concentration increased by 0.6 +/- 0.4 g/dl at 4 h, 1.3 +/- 1.2 g/dl at 8 h, and 2.1 +/- 0.8 g/dl at 12 h. This increase in alveolar protein concentration was proportional to the volume of liquid removed from the lungs. beta-Adrenergic agonist therapy with terbutaline (10(-5) M mixed with the instilled plasma) doubled the volume of liquid cleared from the lungs over 4 h, and the alveolar protein concentration increased proportionally. However, lung liquid clearance in dogs that were treated with beta-agonists was proportionally (50%) less than in sheep treated with beta-agonists. The slower liquid clearance in dogs compared with sheep cannot be explained by differences in hemodynamics, pulmonary blood flow, anesthesia, mode of ventilation, or alveolar surface area.(ABSTRACT TRUNCATED AT 250 WORDS)

Removal of pleural liquid and protein by lymphatics in awake sheep.

The contribution of the parietal pleural lymphatics to pleural liquid and protein removal is unclear. We asked two questions. What is the rate of removal of sterile, artificial hydrothoraxes in awake sheep? What percentage is removed through parietal pleural lymphatics? Three days after the placement of a rib capsule in 18 sheep, we instilled a 10 ml/kg 1.0 g/dl autologous protein solution with labeled albumin and erythrocytes through the capsule into the pleural space. Erythrocytes were used as a marker for lymphatic flow. We measured terminal pleural liquid volume and radioactivity at periods from 2 to 48 h. In three sheep, we obtained a third volume measurement at 6 h by the volume of dilution technique. We found that hydrothorax removal could be described by a linear function with a constant rate: 0.28 +/- 0.01 ml.kg-1.h-1 (mean +/- SE) for the grouped data, and 0.20, 0.28, and 0.31 ml.kg-1.h-1 for the individual sheep. At 24 h, erythrocyte clearance was 89 +/- 16% (mean +/- SD) that of liquid and albumin clearance. We conclude that in awake sheep with large hydrothoraxes, pleural liquid and protein are removed at a rate of 0.28 +/- 0.01 ml.kg-1.h-1 (mean +/- SE) and lymphatics are responsible for at least 89% of this removal.

Pleural effusions and pulmonary edema.

Pleural effusions are a common clinical problem, yet the mechanisms of pleural fluid formation have only recently been investigated. In this article, the anatomy and physiology of the normal pleural space is discussed, as well as the pathophysiology of pleural effusion formation.