Significance of biochemical markers in early detection of canine lung allograft rejection.

To evaluate the significance of bronchoalveolar lavage fluid, levels of tumor necrosis factor-alpha (TNF), gamma-interferon, interleukin 2, and soluble IL-2 receptor in early detection of canine lung allograft rejection, bronchoalveolar lavages were performed serially in mongrel dogs before and after single lung transplantation. The dogs were divided into three groups. Group 1 (control group) consisted of one in which neither donor nor recipient dogs were treated with cyclosporine. In group 2 (CsA-pretreated group) only donors were treated with CsA orally at a single dose of 20 mg/kg/day for 3 days prior to single lung transplantation. In group 3 only recipients were treated with CsA orally at a single dose of 20 mg/kg/day for a short period of 9 days after single-lung transplantation. Marked elevation was found of TNF, IFN-gamma, IL-2, and IL-2R in BALF obtained from the grafted lungs in group 1 and group 2 dogs. The levels of these markers were significantly higher than those obtained from the normal, native lungs (P less than 0.05). Two of three recipients in group 2 had pneumonia in the native lungs on day 10 after single-lung transplantation. All markers except IFN-gamma in BALF obtained from the infected native lungs were also increased, but the titers were less than those obtained from the grafted lungs at the same time. There were significantly higher levels of TNF, IL-2, and IL-2R present in the BALF of grafted lungs of dogs in group 1 than group 2 (P less than 0.05). In group 3, BALF levels of these markers from the grafted lungs were not significantly different from those of the normal and native lungs during the period of CsA treatment after single-lung transplantation. On various days after discontinuation of CsA treatment, BALF levels of all markers began to rise. Abnormal levels of BALF markers obtained from the grafted lungs heralded the appearance of abnormalities detected by chest x-ray films. Our study suggests that serially measuring BALF levels of TNF, IFN-gamma, IL-2, and IL-2R may serve as a useful means in monitoring the immunologic status of canine lung allografts and in the early detection of lung allograft rejection. The role of BALF IFN-gamma in distinguishing lung allograft rejection from pulmonary infection needs further studies.

Increased expression of MHC class II antigens in rejecting canine lung allografts.

Expression of major histocompatibility complex class II antigens was investigated in the normal lungs and in lung allografts of mongrel dogs after single-lung transplantation. Cryostat sections were stained with an indirect immunoperoxidase technique that used B1F6 and 7.5.10.1 as anti-MHC class II monoclonal antibodies. In the normal lungs and native lungs of the recipient dogs after single-lung transplantation, only some cells of lymphoid tissue and macrophages/dendritic cells were MHC class II-positive. During acute rejection, increased infiltration with MHC class II-positive cells in perivascular, peribronchial, and interstitial areas and intraalveolar spaces was found in lung allografts. In addition, expression of MHC class II antigens was induced on the bronchial epithelium and vascular endothelium. Induced expression of MHC class II antigens on the bronchial epithelium and vascular endothelium in rejecting lung allografts was found as early as two days after single-lung transplantation. The intensity of MHC class II antigen expression on bronchial epithelium and vascular endothelium in graft lungs increased with the progression of rejection response and directly correlated with the bronchoalveolar lavage fluid (BALF) levels of biochemical markers, as tumor necrosis factor alpha, gamma-interferon (IFN-gamma), interleukin 2 (IL-2) and soluble interleukin 2 receptor (SIL-2R). Abnormal expression of MHC class II antigens on bronchial epithelium and vascular endothelium and abnormal elevation of BALF levels of the cytokines in lung allografts could be prevented by cyclosporine (CsA) treatment. Our results suggested that MHC class II antigen expression could be induced on the bronchial epithelium and vascular endothelium of canine lung allografts during acute rejection. This abnormal expression of MHC class II antigens on bronchial epithelium and vascular endothelium of graft lungs may serve as a specific index for diagnosis of lung allograft rejection when infection as an inducing factor can be excluded. Furthermore, bronchial epithelium and vascular endothelium of lung allografts have become MHC class II-positive, and are likely to be the targets for low-grade rejection, resulting in the development of bronchiolitis obliterans and occlusive vascular disease in lung allografts.

MHC class II antigens on canine bronchoalveolar cells.

To evaluate the expression of MHC (major histocompatibility complex) antigens on canine bronchoalveolar cells (BAC), bronchoalveolar lavages (BAL) were performed in mongrel and German shepherd dogs. MHC class II antigens on canine BAC and peripheral blood mononuclear cells (PBMC) were detected by monoclonal antibodies (mAbs) B1F6, 7.5.10.1 and Q5/13 recognising canine MHC class II antigens, using cytofluorometry. These mAbs reacted with more than 20% of BAC and PBMC in both breeds of dog. The percentage of MHC class II positive cells in BAC were lower than those in PBMC. There was no significant difference in the percentages of MHC class II positive BAC and PBMC in mongrel and German shepherd dogs. To further identify the expression of MHC class II antigens on BAC, the cells were separated into adherent and nonadherent cells by petri dish adherence. The percentages of MHC class II positive cells in adherent and non-adherent cell populations were similar. Nearly half the lymphocytes in normal BAC were T cells detected by mAbs F3-20-7 and 1A1; B cells were scarce and represented less than 10% of nonadherent cells. Immunoprecipitation by anti-MHC class II mAbs, and SDS-polyacrylamide gel electrophoresis (SDS-PAGE) revealed MHC class II-like molecules on canine BAC and PBMC. After stimulation with phytohaemagglutinin (PHA), the percentages of class II positive cells in BAC and PBMC were significantly increased. Thus, these anti-MHC class II mAbs may prove to be of advantage in experiments designed to evaluate the changes in class II antigen expression on canine BAC during the course of immune response in the lung, as in pulmonary allograft rejection.

The effect of cyclosporine on expression of class II major histocompatibility complex antigens on bronchoalveolar cells and peripheral blood mononuclear cells.

To evaluate the effect of cyclosporine (CsA) on the expression of class II major histocompatibility complex (MHC) antigens on bronchoalveolar cells (BAC) and peripheral blood mononuclear cells (PBMC), BAC and PBMC were obtained from mongrel dogs before and during CsA treatment. Expression of MHC class II antigens on BAC and PBMC were detected by monoclonal antibodies (Mabs) B1F6, 7.5.10.1 and Q5/13, which recognized canine MHC class II antigens, using cytofluorometry. Total cell counts and cell differentials of canine BAC showed no significant difference before or during CsA treatment (P greater than 0.05). Anti-MHC class II Mabs used in this study reacted with 21-51% of canine BAC and with 31-69% of PBMC. After stimulation with phytohaemagglutinin (PHA) the percentages of MHC class II positive BAC and PBMC were significantly increased (P less than 0.001). Whole blood levels of CsA were 315 +/- 76 (mean +/- SD) ng/ml and 343 +/- 57 ng/ml on days 7 and 14 during CsA treatment at an oral dose of 20 mg/kg/day. During CsA treatment there was no significant difference in the percentages of MHC class II positive BAC and PBMC compared with data obtained before CsA treatment (P greater than 0.05). We likewise failed to observe a suppressive effect of CsA on the increased expression of MHC class II antigens on BAC and PBMC induced by PHA (P greater than 0.05). In summary, at an oral dose of 20 mg/kg/day for a period of two weeks, our results show that: (1) CsA does not affect the total cell counts and cell differentials of canine BAC; (2) CsA does not reduce the basal expression of MHC class II antigens on canine BAC and PBMC; (3) CsA does not suppress the increased expression of MHC class II antigens on canine BAC and PBMC induced by PHA.

The effects of high-fat and high-carbohydrate diet loads on gas exchange and ventilation in COPD patients and normal subjects.

Reducing the CO2 production (VCO2) is a plausible means to lower the ventilatory demand in the treatment of patients with COPD. The purpose of this study was to examine the effects of high-fat and high-carbohydrate (high-CHO) diet loads on gas exchange and ventilation in the COPD patients and normal subjects. The percentage of changes in the averaged values of VCO2, O2 consumption (VO2), respiratory quotient (RQ), minute ventilation (VE), and end-tidal CO2 (ETCO2) measured by a mass spectrometer for 5 min every 30 min after the diet were compared between diets and between study subjects. Compared with the high-fat diet, the high-CHO diet can lead to significantly higher levels of VCO2, VO2, RQ, and VE in the COPD patients 30 to 60 min after the diet, and the differences can last for about 1.5 h. The comparison between COPD patients and normal control subjects also showed that the high-CHO diet load can result in significantly higher levels of VCO2, VO2, and VE, and significantly lower level of ETCO2 in the COPD patients, whereas the high-fat diet cannot. In addition, enhanced thermic effect of food within 150 min (TEF150) occurred in the COPD patients as compared with that of normal controls, and the increase in TEF150 occurred only with the high-CHO diet. This study suggested that a high-fat diet is more beneficial to the COPD patient than a high-CHO diet, and that the gas exchange and energy utilization of the COPD patients following a high-CHO diet might be different from that of normal control subjects.

Postural effect on gas exchange in patients with unilateral pleural effusions.

The effect of body position (right and left lateral decubitus positions) on arterial oxygen tension (PaO2) and the relationship between this postural effect on gas exchange and pulmonary function were evaluated in 21 patients who had unilateral pleural effusions without roentgenographic and bronchoscopic evidence of bronchopulmonary disorders. Our results indicated that a positional influence on gas exchange existed in these patients. We failed to find a consistent relationship between the size of effusion estimated by chest roentgenogram and alterations in PaO2 during different positions. Postural change did affect gas exchange in the patients with unilateral pleural effusions and this postural effect on gas exchange was highly correlated with their FEV1 and FVC. This may be of clinical significance in managing such patients.

Effect of body position on gas exchange in patients with unilateral central airway lesions. Down with the good lung?

In this study, we evaluated the effect of body position (erect, supine, and two decubitus positions) on gas exchange (alveolar-arterial PO2 difference [AaPO2]) in 35 patients who had various degrees of lung collapse roentgenographically caused by unilateral central airway lesions, with special reference to the difference in AaPO2 between two lateral decubitus positions. The patients were divided into two groups. Group 1 was composed of 23 patients with FEV1/FVC > 70 percent. In group 2, there were 12 patients with FEV1/FVC < 70 percent. Our results showed that the mean AaPO2 of group 1 patients was least in the lateral decubitus position with normal lung down (AaPO2N), followed by those in the supine position (AaPO2S), in the lateral decubitus position with lesioned lung down (AaPO2L), and in the erect position (AaPO2E). There was no significant difference in AaPO2 obtained in four positions. However, a significantly negative correlation was found between AaPO2NL (AaPO2N minus AaPO2L) and patient's FEV1 (p < 0.05). In group 2 patients, the mean AaPO2E was least, followed by AaPO2L, AaPO2N, and AaPO2S. The changes of body position did not significantly affect gas exchange in group 2 patients. Unlike previous reports, the present study showed that AaPO2N was not exclusively less than AaPO2L in our patients. AaPO2N was higher than AaPO2L in 11 of 23 in group 1 and in 5 of 12 in group 2 patients. In summary, our results indicated that positional changes did not significantly affect gas exchange in the patients with lung collapse roentgenographically caused by unilateral central airway lesions and the dogma "Down with the good lung" could not be applied to these patients flawlessly.

Effects of body position and age on membrane diffusing capacity and pulmonary capillary blood volume.

The effects of body position and age on the membrane diffusing capacity (Dm), pulmonary capillary blood volume (Vc), and the single breath carbon monoxide diffusing capacity (Dco) were evaluated in the erect (sitting) and supine positions in 16 normal young men (under 40 years old, younger group) and in 13 older men (over 40 years old, older group). Dm and Vc were estimated by several measurements of the Dco at increasing alveolar oxygen tension (PAO2). The results showed that Dco, Dm, Vc, and Kco (Dco corrected by alveolar volume) decreased with age in both positions. The differences in Dco, VC, and Kco between the two positions (supine minus the erect position) also decreased with age. The mechanisms of the increases in Dco in the supine position remain to be explained but may be due to a change in pulmonary capillary shape from an elliptical (erect position) to a circular configuration (supine position) since Vc increased more than Dm on assuming the supine position. The findings may be of clinical importance since many physicians have attempted to utilize a reduction in the positional change in Dco as a potential marker of disease.

Measurements of components of resistance to breathing.

Total respiratory resistance (Rrs), pulmonary resistance (RL), and airway resistance (Raw) of 12 male patients with chronic obstructive lung disease were measured by the partial occlusion method, intraesophageal balloon technique, and body plethysmography, respectively. Chest wall resistance (Rew) and lung tissue resistance (Rti) were computed. Percentages of Rew/Rrs, RL/Rrs, Raw/Rrs, Rti/Rrs, Raw/RL, and Rti/RL were calculated. The magnitude of the components of resistance to breathing of this study and the data appearing in the literature are compared. Wide variation between the data reported by various authors was observed. The possible causes of these variations are discussed.

Comparison between short-term and long-term post-operative evaluation of sleep apnoea after uvulopalatopharyngoplasty.

For a long time uvulopalatopharyngoplasty (UPPP) has been used to treat the obstructive sleep apnoea syndrome (OSAS). The diverse surgical effects, the inadequate understanding of operation effect consistency, the possibility of disease progression, and the few reported papers for long-term evaluation after UPPP aroused our interest in designing this study. Fifteen OSAS patients who had undergone UPPP with pre-operative, initial post-operative and long-term post-operative polysomnographic studies were included in this study. Long-term post-operative polysomnography was undertaken more than five years after surgery. The polysomnographic evaluations included respiratory disturbance index (RDI), duration of saturation SaO2 < 85 per cent (DOS), and the lowest O2 saturation (LOS). Amongst them, 10 patients with initial post-operative RDI reduction > 50 per cent were considered responders. In these responders, the long-term follow-up results of all three parameters showed improvement compared to the pre-operative data. In a comparison between the initial and long-term post-operative sleep study results, LOS and DOS showed no significant difference. However, the long-term post-operative RDI result became significantly worse. More than 80 per cent of all cases had subjective symptomatic improvement in the long-term post-operative evaluation. The subjective improvement after operation is not adequately correlated to the polysomnographic result. We suggest that long-term follow-up for patients after UPPP is necessary.

[Effects of uvulopalatopharyngoplasty in obstructive sleep apnea syndrome].

Thirty-one patients with obstructive sleep apnea syndrome underwent uvulopalatopharyngoplasty (UPPP). After three months, the average apnea/hypopnea index (AHI) decreased from 352.2 +/- 138.2 (mean +/- SD) to 182.2 +/- 140.4 episodes/hr and the duration of oxygen desaturation (less than 85%) decreased from 38.4 +/- 48.6 to 13.2 +/- 25.8 minutes. Although only 51.6% patients had a reduction of AHI greater than 50%, a questionnaire study revealed that most patients had subjective improvement of clinical symptoms and only mild complications were noted. We tried to find out the correlation between the efficacy of UPPP and the severity of obstructive sleep apnea and obese but failed. It is concluded that UPPP is the treatment of choice for obstructive sleep apnea syndrome in selective patients.

[Age and pulmonary function testing in predicting postoperative morbidity after thoracic surgery].

In order to evaluate whether age and pulmonary function testing may predict postoperative morbidity and mortality in the patients having received thoracic surgery, 203 patients were included in this study. Spirometry, flow volume curve, lung volume determination and arterial blood gas analysis were performed in all of them. Postoperative complications were classified into respiratory complications including pneumonia, purulent bronchitis, atelectasis, respiratory failure and so on; and non-respiratory complications including subcutaneous emphysema, internal bleeding, stump leakage, dysarrythmia and so on. Of the 117 patients over 65 years of age, 27 (23.1%) had postoperative respiratory complications, 27 (23.1%) had non-respiratory complications, and 7 (5.93%) expired postoperatively. Of the 86 patients under 65 years of age, 21 (24.4%) had postoperative respiratory complications and 9 (7.6%) had postoperative non-respiratory complications, but one expired. The incidences of postoperative mortality and non-respiratory complications were both higher in the patients over 65 years of age (p less than 0.05). Our results indicated that age is a risk factor of thoracic surgery, even if the pulmonary function testing meet the surgical criteria.

Body position, membrane diffusing capacity and pulmonary capillary blood volume in chronic bronchitis and pulmonary emphysema.

BACKGROUND: The effect of body position on diffusing capacity and its components, membrane diffusing capacity (Dm) and pulmonary capillary blood volume (Vc), in patients with chronic obstructive pulmonary disease (COPD) has remained elusive. This study was designed to evaluate the effect of body position on diffusing capacity for carbon monoxide (DLco), Dm and Vc in male patients with chronic bronchitis and pulmonary emphysema. METHODS: Pulmonary function tests including spirometry and lung volume were assessed in the erect position, and DLco, Dm and Vc were measured in the erect and supine positions in a random order in 17 men with chronic bronchitis and 19 men with pulmonary emphysema. RESULTS: Spirometry results and lung volumes were comparable between both groups of patients; however, significantly lower values of DLco and Kco (DLco corrected by alveolar volume, VA) were observed in the emphysema than in the bronchitis group. In the bronchitis group, Kco and Vc were significantly higher in the supine than in the erect position, but Dm was significantly lower in the supine position. Alternation of body position did not significantly affect DLco and its components in the emphysema group. DLco, Kco and Vc in both the erect and supine positions were significantly higher in the bronchitis than in the emphysema group. Vc-SE (SE, the data in the supine minus those in the erect position) was also significantly higher in the bronchitis group. In the bronchitis group, DLco-SE was significantly correlated with Dm-SE and Vc-SE. However, Kco-SE was highly correlated with Dm-SE. In the emphysema group, DLco-SE and Kco-SE were highly correlated with Vc-SE only. CONCLUSIONS: An increase in Vc in the supine position may account for the postural effect on Kco in bronchitis patients. In patients with pulmonary emphysema, decreased DLco and an absence of postural effect on DLco and its components may be due to a widespread abnormality of the pulmonary capillary bed. These findings may be of value in elucidating the difference in mechanisms of impaired gas exchange between patients with chronic bronchitis and pulmonary emphysema.

Total respiratory resistance in chronic obstructive pulmonary disease.

Using a recently described automated system, we measured total respiratory resistance (Rrs) of 59 patients with obstructive lung disease during spontaneous tidal breathing. We also measured airway resistance (Raw) and various other indices of pulmonary function. The results demonstrate that this system gives values of Rrs which correlate well with other objective measures of the severity of obstructive lung disease. It can also be used to detect changes in resistance after inhalation of a bronchodilator. In 10 patients we measured Raw during tidal breathing and computed the total non-airway resistance (Rnaw) as the difference between Rrs and Raw. Rnaw made up a larger portion of Rrs than would be expected in these patients. These results could not be accounted for by differences in breathing frequency, and may instead have been caused by differences between the times in the ventilatory cycle at which Rrs and Raw were measured. We cannot exclude the possibility that Rnaw was abnormally elevated in these patients.

Effects of ascites and body position on gas exchange in patients with cirrhosis.

The effects of ascites and body position on gas exchange were evaluated in 22 male cirrhotics. All underwent spirometry and plethysmography in the sitting (erect) position. Single breath carbon monoxide diffusing capacity (DLco) was measured in the erect and supine positions in a random sequence. A significantly negative correlation was found between Kco (DLco corrected by alveolar volume [VA]) and lung volumes. DLco was significantly higher in the erect than in the supine position. On the other hand, Kco was significantly higher in the supine position. The differences of DLco and Kco between the erect and supine positions (the data in the supine minus those in the erect position) correlated highly with FEV1 and FVC. Thirteen patients underwent large volume paracentesis, and pulmonary function tests were done one day before and after paracentesis. Lung volumes and DLco increased significantly after paracentesis. In contrast, Kco decreased significantly. A significantly negative correlation was found between the change of Kco before and after paracentesis and that of lung volumes (the data after minus those before paracentesis). There was no remarkable change in the differences of DLco and Kco between the two positions after paracentesis. It is concluded that ascites may prevent further worsening of gas exchange and attenuate the postural effect on gas exchange in cirrhotic patients with significant amounts of ascites.

Effect of large-volume paracentesis on pulmonary function in patients with cirrhosis and tense ascites.

The effect of large-volume paracentesis on lung function was evaluated in 12 male patients with cirrhosis. All underwent pulmonary function tests including spirometry, plethysmography and single-breath carbon-monoxide diffusing capacity 1 day before and after paracentesis. The amount of ascitic fluid removed ranged from 3.6 to 131 (mean +/- SD, 7.4 +/- 3.01). After paracentesis, forced vital capacity, forced expiratory volume at 1 s, total lung capacity, functional residual capacity, inspiratory capacity, expiratory reserve volume, diffusing capacity and alveolar volume increased significantly. In contrast, Kco (diffusing capacity corrected by alveolar volume) decreased significantly. After paracentesis, the increase in diffusing capacity was highly correlated with lung volumes and the amount of removed ascitic fluid. Nevertheless, a significantly negative correlation was found between the change of Kco before and after paracentesis and that of lung volumes. The increase in lung volumes and ventilation to the lower lungs with unfavorable ventilation-perfusion matching might explain the discrepancy between changes in diffusing capacity and Kco after large-volume paracentesis. In conclusion, these results suggest that pulmonary function in patients with cirrhosis and tense ascites is partly improved by large-volume paracentesis. Large-volume paracentesis might be useful for symptomatic relief in selected patients with tense ascites.

Therapeutic effects of diuretics and paracentesis on lung function in patients with non-alcoholic cirrhosis and tense ascites.

BACKGROUND/AIMS: Ascites may cause or aggravate pulmonary dysfunction in patients with liver cirrhosis. Diuretics and paracentesis are the main therapies for ascites. The aim of the present study was to evaluate and compare the therapeutic effects of diuretics and large-volume paracentesis on lung function in 26 male patients with non-alcoholic cirrhosis and tense ascites. METHODS: The patients were divided into two groups. Group A was composed of 13 subjects who were treated with diuretics including spironolactone (100-400 mg/day) and furosemide (80-320 mg/day). In group B, 13 subjects received large-volume paracentesis plus intravenous albumin (6-8 g/l ascites removed). Pulmonary function tests including spirometry, plethysmography, single-breath carbon-monoxide diffusing capacity (DLco) and arterial blood gases, were done 1 day before diuretic treatment and 1 day after termination of the study in group A patients, and 1 day before and after large-volume paracentesis in group B subjects. RESULTS: Before treatment, the clinical and laboratory data were comparable between the two groups. After treatment, ventilatory function as evidenced by forced expiratory volume in 1 s, forced vital capacity, total lung capacity, functional residual capacity and expiratory reserve volume, and DLco increased significantly in both groups. Arterial PO2 and PCO2 increased significantly and AaPO2 (alveolar-arterial PO2 difference) decreased significantly in the subjects treated with diuretics. Nevertheless, paracentesis did not improve arterial blood gases. The changes in lung volumes, DLco and PaO2 after treatment (the data after minus those before treatment) were comparable, except that a significant decrease in AaPO2 was observed in the diuretic group. CONCLUSIONS: Both diuretic therapy and large-volume paracentesis significantly improved the ventilatory function in patients with tense cirrhotic ascites. In terms of oxygenation improvement as evaluated by AaPO2, diuretic treatment may be superior to large-volume paracentesis.