Current status of lung transplantation for cystic fibrosis.

Lung transplantation has emerged as an acceptable option for the management of cystic fibrosis patients with endstage lung disease. Heart-lung transplantation and, more recently, double lung transplantation have been successfully performed in this group of patients. The choice of operation, so far, has been based on the surgeon's preference and experience as well as the cardiac function of the patient. Each of the procedures has advantages and disadvantages. This article reviews the current worldwide experience in lung transplantation for patients with cystic fibrosis and highlights the controversies involved in the selection of patients and procedure.

The early release of interleukin-2, tumor necrosis factor-alpha and interferon-gamma after ischemia reperfusion injury in the lung allograft.

A period of cold and warm ischemia is obligatory when performing lung transplantation. Subtle ischemia-reperfusion injury induced in the course of transplantation can pass undetected or cause a short phase of reversible lung dysfunction. We hypothesized that ischemia-reperfusion injury may result in the local release of cytokines that have the capability to mediate acute lung injury early following transplantation. To test this hypothesis, 10 mongrel dogs were subjected to left lung allotransplantation. As performed in the clinical setting, donor lungs were preserved with Eurocollins solution and stored at 4 degrees C for 4 hr, which was followed by 1 hr of warm ischemia. Recipients received standard immunosuppression of cyclosporine, azathioprine, and low dose steroids. Bronchoalveolar lavage (BAL) and open lung biopsies were performed before operation and at approximately 1 hr, 4 hr, 24 hr, and 1 week after transplantation. A significant increase in BAL IL-2 levels was observed 4 hr after surgery (0 hr: 349 +/- 138 pg/ml; 4 hr: 757 +/- 284 pg/ml) (mean +/- SEM) (P < 0.05) which subsequently decreased 24 hr (320 +/- 168 pg/ml) after transplantation. BAL TNF-alpha levels were significantly increased 1 hr after transplantation (P < 0.05) (0 hr: 3.4 +/- 0.65 pg/ml; 1 hr: 13.3 +/- 8.0 pg/ml) returning to baseline after 24 hr (5.8 +/- 2.8 pg/ml). BAL IFN-gamma levels also significantly increased 1 and 4 hr after transplantation (0 hr: 7.2 +/- 2.1 pg/ml; 1 hr: 68.2 +/- 49.2 pg/ml; 4 hr: 301 +/- 131 pg/ml) (P < 0.05). This decreased back to baseline after 24 hr and 1 week (5.2 +/- 1.2 pg/ml and 9.7 +/- 7.9 pg/ml, respectively). There were no changes detected in plasma levels of cytokines. Histology showed evidence of grade 1-2 rejection after 1 week. We conclude that subjection of a lung allograft to standard periods of cold-warm ischemia will result in a temporary early elevation of IL-2, TNF-alpha, and IFN-gamma detectable only in the bronchoalveolar compartment. Such local increase in cytokines in the lung allograft may play an important role in the development of early allograft dysfunction.

Lectin-dependent cell-mediated cytotoxicity and natural killer function in rejecting and infected lung allografts.

Differentiation between rejection and infection of lung allografts remains difficult. The effects of these two pathologic entities on the cytolytic activity of bronchoalveolar lavage (BAL) and PBL were investigated. Left lung allotransplantation was performed on 16 mongrel dogs of which 12 were available for complete studies. All animals received CA, AZA, and PRED for 2 weeks. Four grafts developed left lower lobe Gram negative pneumonia. The eight remaining recipients progressed gradually to severe rejection after acute reduction of immunosuppression. Cytolytic activity of blood and left lung BAL lymphocytes was quantitated by the natural killer (NK) and lectin-dependent cell-mediated cytotoxicity (LDCMC) assays. Two additional groups serving as controls were either given a 10-day course of immunosuppressants or had right lower lobe pneumonia induced by transbronchial inoculation of gram negative bacteria. Immunosuppressed control animals showed significant depression of PBL and BAL lymphocyte LDCMC and NK activity. Similarly, BAL lymphocytes expressed very low LDCMC in normal allografts (2.8 +/- 0.8%). Once rejection developed and progressed, LDCMC became significantly higher (15.6 +/- 2.2 and 52.7 +/- 2.8% in mild and severe rejection, respectively). There was no detectable NK activity in rejecting lung allografts. BAL lymphocytes from infected allografts, on the other hand, showed an elevation of both NK and LDCMC activity (9.1 +/- 1.1 and 14.6 +/- 1.0%, respectively). Similarly, bacterial pneumonia in control animals manifested an increase in NK and LDCMC activity in lung and blood. PBL lymphocytes of lung allograft recipients, however, had increased NK and LDCMC activity in both rejection and infection. LDCMC/NK activity ratio (LM/NK index) of lung lymphocytes was significantly higher in rejecting allografts (11.2 +/- 1.0 and 12.4 +/- 1.6 for mild and severe rejection, respectively) than in infected ones (1.2 +/- 0.3, P < 0.0001). It appears, from this study, that rejection of the lung allograft results in alterations in BAL lymphocyte phenotypes and functions that differ from those associated with bacterial infection. Such differences may be useful in distinguishing episodes of acute allograft rejection from bacterial infection.

Altered nonspecific lymphocyte cytotoxicity in bronchoalveolar lavage of lung transplant recipients: can it be useful in monitoring rejection or infection?

A reliable method for determining the adequacy of immunosuppression of the lung allograft and the absence of rejection or infection does not exist. The purpose of this study is to evaluate the potential role of bronchoalveolar lavage (BAL) in monitoring the adequacy of immunosuppression of lung allografts and in identifying the possible presence of acute rejection (AR) or infection. Thirty-one consecutive lung transplant recipients were subjected to bronchoscopy, transbronchial biopsy, and BAL either as routine surveillance or for decline in lung function (n=68 episodes: 27 normal, 17 infections, six grade IAR, 10 grade II-III AR, and eight obliterative bronchiolitis). Diagnosis was always confirmed histologically and by microbiological workup. Harvested cells underwent phenotypic analysis, and T lymphocytes were subjected to nonspecific lectin-dependent cell-mediated cytotoxicity (LDCMC) and natural killer cytotoxic assays. BAL from normal grafts predominantly contained macrophages (72.8+/-4.4%), with lower neutrophil (13.9+/-4.1%) and lymphocyte (13.2+/-2.2%) populations. Grade II-III AR and infection were associated with an increase in the percentage of neutrophils (43.3+/-8.3% and 33.2+/-3.6%, respectively, P=0.02). BAL of normal allografts contained T cells with low LDCMC (7.4+/-4.5%) and natural killer cytotoxicity (6.3+/-3.4%), whereas grade II-III AR was associated with a significant elevation in LDCMC (32.5+/-11.6%, P=0.019). Pulmonary infection, regardless of its type, was associated with significant elevation in BAL natural killer cytotoxicity (23.9+/-4.9%, P=0.033). Patients with obliterative bronchiolitis, on the other hand, had a mild elevation in the percentage of neutrophils and lymphocytes in BAL, which did not reach statistical significance. However, BAL T-cell LDCMC was significantly elevated (37.6+/-13.7%, P=0.019) compared with normal and infected allografts. We conclude that phenotypic and nonspecific cytotoxic T-cell analysis of BAL, when complimented with microbiological studies, may be useful in surveillance of lung transplant recipients and in determining whether allografts are likely to be quiescent, or possibly affected by acute/chronic rejection or infection, necessitating further definitive action.

Immunohistochemical localization of nitric oxide synthase and the oxidant peroxynitrite in lung transplant recipients with obliterative bronchiolitis.

BACKGROUND: Obliterative bronchiolitis (OB) is a disease affecting a large percentage of lung and heart-lung transplant recipients. Histologically, the disease is characterized by inflammation, cellular proliferation, and obliteration of terminal airways. METHODS: We investigated the production of inducible and constitutive nitric oxide synthases and peroxynitrite by immunohistochemistry in the lungs of control subjects (n=14) compared with those of transplant recipients with OB (n=8). RESULTS: Strong immunoreactivity for inducible nitric oxide synthase and nitrotyrosine, a marker of protein nitration by peroxynitrite, was seen in inflammatory cells, airway epithelium, and vascular endothelium of patients with OB, compared with little immunoreactivity in control lungs. Immunoreactivity for constitutive nitric oxide synthase was abundant in the airway epithelium and vascular endothelium of control lungs, however, it was decreased in airway epithelial cells and arterial endothelial cells of patients with OB. CONCLUSIONS: We conclude that increased formation of the potent oxidant peroxynitrite and decreased production of endothelial nitric oxide may contribute to the functional and morphological abnormalities of OB.

Endothelin receptor antagonist improves pulmonary hemodynamics during lung ischemia/reperfusion injury.

BACKGROUND: We have previously shown that elevated release of endothelin-1 is associated with increased pulmonary vascular resistance (PVR) immediately after reperfusion of the transplanted lung. In the present study, we investigated the effect of ET receptor blockage on pulmonary hemodynamics and function in an ex vivo lung reperfusion model after 6 hr of cold ischemia. METHODS: Eighteen rabbits were divided into three groups: no ischemia followed by 3 hr of reperfusion (group I) and 6 hr of cold ischemia followed by 3 hr of reperfusion with either blood (group II) or blood + SB209670 (mixed ETA/ETB receptor antagonist) (group III). RESULTS: Shortly after reperfusion, mean pulmonary artery pressure, PVR, and pulmonary edema were increased, and pulmonary compliance and PO2 were decreased in group II compared with group I. Treatment with SB209670 resulted in a significant decrease in mean pulmonary artery pressure, PVR, and pulmonary edema, and improvement in pulmonary compliance and PO2. CONCLUSION: The data suggest an important role for ET-1 in lung ischemia/reperfusion injury and that the use of ET receptor antagonist immediately after transplantation may provide a new therapeutic tool in the management of early graft dysfunction.

Alterations in bronchoalveolar lavage and plasma endothelin-1 levels early after lung transplantation.

A temporary increase in pulmonary vascular resistance is observed during the first 24 hr following lung allotransplantation. We hypothesized that such early vascular changes are secondary to endothelial injury by ischemia-reperfusion, and that this may be mediated by an increased pulmonary endothelin-1 production/release. To test this hypothesis, radioimmunoassay was used to analyze endothelin-1 levels in bronchoalveolar lavage and plasma taken before surgery and at 1 hr, 4 hr, 24 hr, and 1 week after transplantation. The study was carried out on 2 groups of mongrel dogs. One group was subjected to left single-lung allotransplantation and the other to autotransplantation. Endothelin-1 levels in the bronchoalveolar lavage samples from the lung allografts were significantly increased at 1 (0.70 +/- 0.18 pg/ml) and 4 (1.84 +/- 0.65 pg/ml) hr after transplantation compared with the preoperative value (0.14 +/- 0.05 pg/ml), and declined at 24 (0.85 +/- 0.84 pg/ml) hr after transplantation. Similarly, plasma endothelin-1 levels in the allografts were significantly increased at 1 (2.0 +/- 0.80 pg/ml) and 4 (2.0 +/- 0.71 pg/ml) hr after transplant when compared with preoperative levels (0.54 +/- 0.09 pg/ml). Plasma endothelin-1 levels, however, remained significantly high after 24 hr (1.4 +/- 0.4 pg/ml; P < 0.007) and decreased after 1 week after transplant (0.89 +/- 0.32 pg/ml). On the other hand, endothelin-1 levels in bronchoalveolar lavage from the autograft group remained relatively unchanged; however, plasma levels showed a significant increase at 4 hr (6.6 +/- 1.8 pg/ml) after transplantation compared with preoperative levels (2.8 +/- 0.38 pg/ml). Elevation of endothelin-1 levels early after lung transplantation may play an important role in early high pulmonary vascular resistance and temporary graft dysfunction.

Immunohistochemical characterization of inflammatory and proliferative events during chronic rejection in rat lung allografts.

BACKGROUND: Chronic rejection is assumed to be the principle cause of airway injury leading to obliterative bronchiolitis (OB) after lung transplantation (Tx). To better understand the contribution of chronic rejection in the development of OB in allografted lungs, we examined the histopathological changes and cytokine expression in inadequately immunosuppressed rat lung allografts. METHODS: Three groups of rats were studied: group I, control nontransplanted Lewis (Lew) rats (n=5); group II, syngeneic Lew-to-Lew isografts (n=25); and group III, Brown Norway-to-Lew allografts (n=25). Groups II and III received two single doses of cyclosporine on postoperative days 2-3. Transplanted animals were killed (n=5) at monthly intervals from 2 months to 6 months after Tx. Resected lungs were stained with hematoxylin and eosin, Masson's trichrome, and Van Gieson's elastin, and immunostained with antisera to interleukin (IL)-1beta, IL-8, and basic fibroblast growth factor (bFGF). The intensity of immunostaining was graded from 0 to 4 (0=no staining, 4=strong staining). RESULTS: In groups I and II, normal airways and vessels were observed. Minimal intensity and distribution of immunostaining for all markers were detected in groups I and II. Group III allografts demonstrated acute grade II-III vascular rejection with mild bronchiolar injury and inflammation at 2 months after Tx. At 6 months after Tx, all allografts demonstrated severe and diffuse chronic vascular rejection. Late airway changes consistent with OB were detected in four of five allografts, however, these lesions were expressed infrequently. Immunohistochemical findings revealed moderate to strong expression for IL-8 and bFGF over the airway epithelium, acute and chronic inflammatory cells, and fibroblasts in allografts at 2 months after Tx. Despite focal development of OB at 6 months, intensity and distribution of immunostaining significantly decreased for all three cytokine markers. CONCLUSIONS: Inadequate immunosuppression of rat lung allografts leads primarily to chronic vascular rejection but fails to induce severe and diffuse development of OB. In this animal model, cytokines IL-1beta, IL-8, and bFGF are likely to play an important role in the early inflammatory phase but not during the late proliferative events of chronic rejection.

Warm ischemia induces alteration in lung immune cell functions.

Warm ischemia is an important factor in early allograft dysfunction. To elucidate cellular events involved in such lung injury, we examined the effects of warm ischemia on the cytotoxic function of lymphocytes retrieved by bronchoalveolar lavage as compared with peripheral blood lymphocytes. Warm ischemia of the lung was induced in eight dogs by crossclamping left hilar structures for 1 hour. Bronchoalveolar cells from ischemia left and unaffected right lungs, as well as blood lymphocytes, were isolated before operation and 2 hours, 72 hours, and 7 days after operation. Lung and blood lymphocytes were assayed for natural killer and lectin-dependent cell-mediated cytotoxicity. Warm ischemia resulted in a significant impairment of natural killer activity within 2 hours of reperfusion (49% of preoperative control cytolysis, p less than 0.01). There was a significant increase in natural killer activity in bronchoalveolar lavage mononuclear cells 72 hours after reperfusion injury (178.4% of preoperative value, p less than 0.01). Interestingly, these functional alterations were not paralleled with changes seen in the peripheral blood lymphocytes or the opposite nonaffected lungs, where the natural killer activity appeared significantly depressed at 72 hours. Similarly, lectin-dependent cell-mediated cytotoxicity was noted to be increased in the bronchoalveolar lavage from the ischemic lung (179.5%, p less than 0.01) but decreased in the bronchoalveolar lavage from the nonaffected lung and peripheral blood lymphocytes at 72 hours after injury. We conclude that warm ischemia is associated with a functional alteration of the local lung immune cells. Such alteration is not observed in cells from the opposite lung or peripheral blood. The observed increase in nonspecific cytotoxicity of bronchoalveolar lymphocytes can be causative in the early damage seen in poorly preserved lung allografts.

Robotic computer-assisted telemanipulation enhances coronary artery bypass.

OBJECTIVES: Totally endoscopic coronary artery bypass grafting depends greatly on perfecting the anastomosis. We tested a new computer-assisted telemanipulation robot (Intuitive Surgical Inc, Mountain View, Calif) in performing endoscopic coronary bypass. METHODS: On-bench anastomoses of the porcine arterial graft to the left anterior descending coronary artery were performed with both direct visualization and conventional surgical instruments (group I), endoscopic 3-dimensional visualization and current endoscopic surgical instruments (group II), direct visualization and endoscopic instruments (group III), 3-dimensional endoscopic visualization and conventional surgical instruments (group IV), and telemanipulation robotic with 3-dimensional endoscopic visualization (group V). Anastomoses (n = 6 in each group) were assessed for time (minutes), quality (good = 3, fair = 2, poor = 1), technical difficulty (easy-difficult: 1-4), and patency (100% = 1, >50% = 2, <50% = 3). RESULTS: Anastomotic time was significantly longer in groups II and III than in groups IV and V (P

Amelioration of pulmonary allograft injury by administering a second rinse solution.

OBJECTIVE: The use of rinse solutions before reperfusing liver allografts has been shown to reduce cell death in rats. Carolina rinse solution (an extracellular solution that contains antioxidants, vasodilators, and other substrates that help prevent ischemia-reperfusion injury) has also been shown to improve liver function clinically in liver transplant recipients. This pilot study evaluates the value of a second pulmonary artery flush before reperfusion of a lung graft. METHODS: Six groups of Sprague-Dawley rats (n = 6 each) were subjected to the following: Group 1 lungs were preserved with modified Euro-Collins solution followed by 24 hours of cold ischemia. Group 2 lungs were treated the same as group 1 but reperfused with blood. Group 3 lungs were preserved in Carolina rinse solution followed by 24 hours of cold ischemia. Group 4 lungs were treated the same as group 3 lungs and then reperfused with blood. Lungs in groups 5 and 6 were preserved with Euro-Collins solution, stored cold for 24 hours, and then rinsed with Euro-Collins or Carolina rinse solution, respectively, before reperfusion with blood. Lungs were subsequently stained with trypan blue solution for 5 minutes. Lung blocks were fixed and embedded in water-soluble methacrylate. Trypan blue--stained nuclei in nonviable endothelial cells and alveolar pneumocytes were counted in 10 different fields. RESULTS: Groups 1 and 3, preserved with Euro-Collins and Carolina rinse solutions for 24 hours but not reperfused with blood, had significantly more viable endothelial cells (groups 1 and 3 vs group 2, p < 0.0001; group 3 vs group 4, p < 0.02) and pneumocytes (group 1 vs groups 2 and 4, group 3 versus group 2, p < 0.0001; group 3 vs group 4; p < 0.035) than groups 2 and 4, which were subsequently reperfused with blood. Groups 5 and 6, which received a second rinse, also had significantly more viable endothelial cells (p < 0.0005) and pneumocytes (p < 0.0001) than control groups, which were not rinsed before reperfusion. CONCLUSIONS: We conclude that damage to pulmonary allografts resulting from prolonged ischemia is accentuated by reperfusion with blood. We also conclude that preservation with a single flush of Euro-Collins or Carolina rinse solution does not offer adequate protection, whereas a second rinse before reperfusion significantly decreases the number of damaged cells within the allograft.

Superior vena cava obstruction secondary to mediastinal lymphadenopathy in a patient with cystic fibrosis.

Superior vena cava (SVC) obstruction most often is a complication of malignant tumors such as lung cancer or lymphoma. The common use of long-term indwelling central venous catheters also has added to the prevalence of SVC obstruction. This report describes the first case of SVC obstruction in a patient with cystic fibrosis due to extrinsic compression from benign reactive mediastinal lymphadenopathy. Although in these circumstances intravascular thrombosis should be ruled out, extrinsic compression from mediastinal lymphadenopathy should be considered.

Techniques for localization of pulmonary nodules for thoracoscopic resection.

Significant advances in surgical equipment, video monitoring, and endoscopic surgical techniques have expanded the role of thoracoscopy to include pulmonary resection. One limitation of the thoracoscopic technique is the loss of manual palpation to identify the nodule that is either too small or too deep beneath the pleural surface. We describe the techniques used in 300 thoracoscopic pulmonary resections that have aided in identification of pulmonary nodules. These techniques include careful preoperative assessment of the computed tomogram, preoperative injection of methylene blue, or a needle localizing system to identify the nodule. Intraoperative techniques include instrument palpation, digital palpation, and intraoperative ultrasonography. It should be possible to identify the majority of pulmonary nodules at the time of thoracoscopy with these localizing techniques. All nodules were successfully identified in our last 200 thoracoscopic resections.

Surgical decompression of a tension pneumomediastinum. A ventilatory complication of status asthmaticus.

A case of status asthmaticus was associated with cardiorespiratory arrest, illustrating rarely reported complications of ventilatory therapy including tension pneumomediastinum and coronary air embolization. Proposed pathophysiologic mechanisms and recommendations for surgical management are discussed.

Differential lung ventilation. Applications beyond the operating room.

Mechanical ventilatory support in the setting of unilateral lung disease offers unique problems in management. When the difference in airway resistance or lung compliance between the two lungs is exaggerated, conventional mechanical ventilation might lead to preferential ventilation with hyperexpansion of one lung and gradual collapse of the other. Differential ventilation has been advocated to avert this problem. We illustrate the use of this technique in the management of two patients with different underlying pathologic conditions.

Airway mucus and epithelial function in a canine model of single lung autotransplantation.

Impaired mucociliary function following lung transplantation has been reported in several human and animal studies. This could be a result of altered ciliary function or mucus properties or both. We assessed airway epithelial function by means of transepithelial potential difference (PD) measurements and physical analysis of mucus. Six mongrel dogs underwent single lung autologous transplantation. Measurements were performed preoperatively and 1, 2, 4, and 10 months postoperatively. At 1 and 2 months postoperatively, there was a significant fall in PD for the transplanted, left mainstem bronchus only (-13.5 +/- 1.7 mV at 1 month and -14.6 +/- 1.7 mV at 2 months postoperatively vs -18.6 +/- 2.3 mV preoperatively, baseline; p < 0.001 for both). The PD values in the small airways, right mainstem bronchus, and the trachea remained unchanged. At 2 months postoperation, the mucus collection rate on the left side was increased (p = 0.03), while the mucus viscoelasticity was decreased (p = 0.04). By 4 months postoperation, all epithelial parameters had returned to baseline, and there was no difference in radioaerosol clearance between the two lungs. The PD decrease and alterations in secretion rate and viscoelasticity reflect disturbed epithelial functional integrity at the site of anastomosis still present at 2 months postoperation. Recovery of bronchial epithelial function and clearance in canine studies of lung autotransplantation after healing of the anastomosis area suggest that persistent impairment of lung clearance observed in some long-term human lung transplantation survivors may be due to other mechanisms such as impaired healing or epithelial function or both, during immunosuppressive therapy. Mucociliary function in the anastomosis area is compromised until complete healing ensues; we speculate that chest physiotherapy may aid in overcoming this obstacle.

A novel charcoal-induced model of obliterative bronchiolitis-like lesions: implications of chronic nonspecific airway inflammation in the development of posttransplantation obliterative bronchiolitis.

OBJECTIVES: In this study, we describe the development of a nonallogeneic animal model of obliterative bronchiolitis-like lesions. Furthermore, we examined whether chronic rejection alone can lead to the development of obliterative bronchiolitis or whether additional nonspecific airway inflammation is required. METHODS: Part I: Rats were intratracheally injected with 0.2 ml of activated charcoal or sorbitol solution (carrier for charcoal control). Animals were put to death beginning at 2 weeks up to 20 weeks. Part II: Animals were divided into three groups: group I, underimmunosuppressed Brown Norway to Lewis lung allografts; group II, charcoal-treated underimmunosuppressed allografts; and group III, charcoal-treated rats. Animals were put to death at 3 months after transplantation. RESULTS: Part I: In charcoal-laden bronchioles, subacute nonspecific airway inflammation was detected at 2 weeks. Slow, subclinical fibroproliferation ensued during the following weeks. Obliterative bronchiolitis-like lesions were observed in 80% of charcoal-treated animals at 12 weeks. Part II: Allografts developed extensive vascular lesions consistent with acute and chronic vascular rejection. Obliterative bronchiolitis-like lesions were scarcely detected. Charcoal-treated allografts demonstrated evidence of diffuse and severe obliterative bronchiolitis-like lesions. CONCLUSIONS: Transtracheal injection of activated charcoal into native lungs results in slowly progressive airway injury and inflammation leading to obliterative airway lesions. Inadequate immunosuppression primarily results in chronic vascular rejection but not obliterative bronchiolitis. Underimmunosuppressed allografts subjected to nonspecific airway inflammation develop obliterative airway lesions that are more prominent than in native lungs. This suggests that a cofactor to chronic rejection is likely necessary for the development of lung transplant obliterative bronchiolitis.

The reversibility of impaired mucociliary function after lung transplantation.

Impairment of mucociliary function occurs after lung transplantation and may predispose patients to repeated pulmonary infections. The purpose of this study is to determine whether and how soon such mucociliary function may recover. Ten dogs underwent left lung autotransplantation. Within 3 weeks five of these dogs underwent study for proximal airway clearance by observation through a bronchoscope of the movement of carbon particles placed at different locations on the tracheobronchial mucosa. The mechanical properties of collected mucus from specific sites were determined by magnetic rheometry. The right lung, which was not operated on, served as a paired control. Similar studies were conducted in the remaining five dogs at 12 weeks after autotransplantation. Lung autotransplantation caused significant depression of proximal airway clearance and a 35% increase in mucous rigidity (p = 0.05) soon after operation. At 12 weeks after operation, there was a partial recovery of proximal airway clearance. Mucous changes were no longer consistent. Histologic and electron microscopic examinations initially revealed focal denudation of ciliated cells and loss of the bronchial glands. At 12 weeks there was a regeneration of cilia and a reappearance of the bronchial glands. We conclude that the mucociliary function, observed to be depressed early after lung autotransplantation, recovers partially during the late postoperative period. Thus the mucociliary functional recovery should be attributed to revascularization rather than to reinnervation, since the latter is unlikely to occur during this period.

Mucociliary function in autotransplanted, allotransplanted, and sleeve resected lungs.

Tracheobronchial mucociliary function in dogs that underwent left upper sleeve lobectomy was compared with that of dogs that underwent left lung autotransplantation or allotransplantation (n = 5 each). Proximal airway clearance was measured by observing the movement of carbon particles through a bronchoscope. Preoperative and postoperative clearance rates for the right lungs in these dogs were unchanged. Although preoperative clearance rates in the transplanted left lungs were comparable with those of the right lungs, these left lungs were unable to clear the carbon particles during a 15-minute observation period 3 weeks postoperatively. In contrast, preoperative and postoperative clearance rates for the dogs that underwent sleeve resection were unchanged for both lungs. Mucus rigidity was studied by microrheometry and was found to be significantly increased postoperatively for samples collected from the autotransplanted and allotransplanted lungs than for samples collected from the untreated right lungs. These changes in mucus were noted for forces representing both normal ciliary beat and coughing. Viscoelastic properties of mucus were not significantly altered after sleeve lobectomy. Microscopic study showed squamous cell metaplasia and relative disappearance of bronchial glands distal to the anastomosis in all transplanted lungs. These changes were less pronounced in the sleeve resected bronchi. We conclude that changes in rheologic characteristics of mucus can impair mucociliary clearance and may be related to denervation after lung transplantation. Bronchial devascularization may have an additional effect of altering mucosal structures and function in the early postoperative period after lung transplantation. These effects are avoided by preserving peribronchial tissue in sleeve resection.

Diltiazem improves cyclosporine dosage in cystic fibrosis lung transplant recipients.

Maintenance of therapeutic blood levels of cyclosporine in lung transplant patients with cystic fibrosis can be challenging. In addition, total daily dosage can be high when compared with patients who do not have cystic fibrosis. We report the advantage of adding diltiazem to decrease the cyclosporine dosage and maintain adequate therapeutic levels. Diltiazem 60 mg twice daily was initiated in four patients with cystic fibrosis and in four patients who did not have cystic fibrosis. In patients with cystic fibrosis, mean dosage and mean diltiazem efficacy ratio (dose milligrams per kilograms per day/cyclosporine blood level) were significantly reduced. Dosage was reduced from 13.9 +/- 8 to 8.1 +/- 2.6 mg/kg mean +/- standard deviation). The latter was similar to patients who do not have cystic fibrosis (6.5 +/- 1.8 mg/kg). Diltiazem efficacy ratio was reduced from 85 +/- 22 to 27 +/- 4. In patients who did not have cystic fibrosis, the ratio was significantly reduced from 42 +/- 13 to 19 +/- 3. Resting blood pressure, pulse, and serum creatinine levels remained normal or normalized. Although cyclosporine dosage was not significantly reduced by adding diltiazem in patients who did have cystic fibrosis, adequate cyclosporine blood levels were achieved. We conclude that the addition of diltiazem can be useful in the maintenance of adequate cyclosporine therapy in lung transplant recipients who do or who do not have cystic fibrosis.