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CYCLOSPORIN A IN EXPERIMENTAL LUNG TRANSPLANTATION

Cyclosporin A (Cy A) has been used in combination with low-dose azathioprine (2 mg/kg/day for 14 days) or other immunosuppressives to treat 13 canine lung allograft recipients. Two of five dogs treated with Cy A and azathioprine survive at 13 and 6 months, respectively, with normal lung function and no evident rejection. The other three dogs in this group survived for over 5 months despite evidence of rejection which was reversed with methylprednisolone (50 mg/kg/day for 3 to 5 days). The addition of prophylactic corticosteroids or their substitution for azathioprine resulted in decreased survival without preventing rejection better. The lung allograft rejection that occurred with Cy A was usually later in onset and more easily reversed by corticosteroids than the lung rejection that occurred with standard immunosuppression. Cy A rejection was also sometimes qualitatively different. Perivascular mononuclear cell cuffs and a proportionally greater decrease in allograft perfusion with respect to ventilation were often more prominent than in rejection with standard immunosuppression. In some instances, decreased allograft perfusion evidenced rejection while the plain chest roentgenogram and ventilation remained normal. Except for infection, which only occurred in animals receiving prophylactic corticosteroids, there was no toxicity from Cy A. These findings indicate that this drug is the safest, most effective immunosuppressive agent yet available for use in lung transplantation.

Bronchial anastomotic healing in canine lung allotransplants treated with cyclosporine

Bronchial anastomotic healing was evaluated in 22 long-term-surviving canine lung allotransplant recipients treated with cyclosporine as the major immunosuppressive agent. Mean survival in these dogs was over 155 days, and 4 animals survived 1-3 years. Bronchial anastomotic complications were limited to 5 cases of minimal (less than 15%) bronchostenosis. The bronchial anastomoses became somewhat edematous and friable during rejection episodes, but no clinically serious sequelae--such as hemorrhage, peribronchial abscess, or bronchial dehiscence--were observed. Gross and microscopic evaluation of the recipient and donor segments of the anastomoses revealed excellent healing, with only scattered areas of inflammatory cells. The decreased frequency and severity of rejection episodes in animals treated with cyclosporine permits early revascularization of the bronchus to take place and reduces the need for other immunosuppressive agents that may interfere with bronchial healing. Cyclosporine is an effective immunosuppressive agent for canine lung allotransplantation and allows normal bronchial anastomotic healing to occur.

Cyclosporin A as the initial immunosuppressive agent for canine lung transplantation: Short-and long-term assessment of rejection phenomena

Cyclosporin A (Cy A) was evaluated as the initial immunosuppressive agent for lung transplantation in unmatched mongrel dogs. Rejection phenomena were assessed by plain chest roentgenograms, histology, radionuclide ventilation-perfusion scans, and by the level of lectin-mediated lymphocyte cytotoxicity in cells obtained by bronchoalveolar lavage. Two groups of lung allograft recipients were studied. One group was treated with Cy A alone and the other was treated with Cy A and a short course of azathioprine (AZA) therapy (2 mg/ kg/day for 14 days). Recipient survival and the nature and severity of rejection phenomena were similar in the two groups. Two morphologically and functionally distinct patterns of rejection occurred with similar frequency in Cy A and Cy A-AZA-treated lung allograft recipients. The first pattern was characterized by extensive changes in plain chest roentgenograms, the presence of interstitial, perivascular, and alveolar mononuclear cell infiltrates in histological sections, both ventilation and perfusion abnormalities on lung scans, and relatively high levels of lectin-mediated T cell cytotoxicity. The second pattern of rejection was characterized by minimal changes on chest films, histological findings limited to perivascular mononuclear cell infiltrates, relatively normal ventilation but abnormal perfusion on lung scans, and significantly lower T cell cytotoxicity. High-dose, short-term treatment with methylprednisolone was usually effective in the reversal of the first type of rejection. In contrast, long-term maintenance prednisone therapy that was begun >30 days after transplantation was necessary to suppress the second pattern of rejection. Our study suggests that Cy A alone provides effective initial immunosuppression for use in lung allotransplantation, although corticosteroid therapy may be required after the 1st month. Preliminary data suggest that it may be possible to discontinue Cy A therapy without evidence of increased lung allograft rejection in some mongrel dogs.

Long-term fate of lung autografts charged with providing total pulmonary function. II. Hemodynamic, functional and angiographic studies.

Four dogs underwent autotransplantation of the left lung with immediate ligation of the right pulmonary artery and survived up to five years. Mean pulmonary artery pressures increased from 15 ± 2 mmHg preoperatively to 23 ± 4 mmHg immediately after operation and remained at the level (24 ± 3 mmHg) up to five years operation. Arterial and venous blood gas values, determined while the animals were breathing ambient air spontaneously under light anesthesia, did not deteriorate with time and were within the normal range. The vascular resistance of the transplanted lungs up to five years after operation were not significantly different from those determined immediately after operation and remained lower than preoperative values, indicating that transplanted lungs retain indefinitely the ability to vasodilate with increased blood flow. Periodic angiography performed from 3–5 years after operation confirmed that the right lungs received no pulmonary blood flow and revealed normal vascular morphology except for moderate dilatation of the large arteries in the transplanted left lung. Thus, single transplanted lungs can provide total respiratory function while carrying the entire pulmonary blood flow at tolerable arterial pressures for at least five years without evidence of functional deterioration.

Long-term fate of lung autografts charged with providing total pulmonary function. I. Light and electron microscopic studies.

Two groups of dogs underwent light and electron microscopic examination of both lungs up to five years after left lung auto-transplantation. In one group of four dogs that had undergone ligation of the right pulmonary artery at the time of left lung autotransplantation, no generalized or consistent lesions were present in the transplant except for slight distension of net capillaries and slight capillary basement membrane thickening. Aside from these minor changes which were probably of no functional significance, most areas of lung examined up to five years after transplantation were normal. In the second group of four dogs that did not have contralateral pulmonary artery ligation at the time of left lung autotransplantation, no consistent abnormality was present in either the transplanted left or nontransplanted right lung. In three animals in this group, widespread normal areas were present bilaterally up to five years after transplantation. One animal in this group had focal changes consistent with chronic pulmonary disease in both of its lungs. Thus, transplanted lungs do not necessarily develop significant late pathologic lesions.

Pulmonary and hemodynamic function in dogs during exercise: effects of lung autotransplantation.

An airtight facemask/mouthpiece assembly has been devised to facilitate the performance of a wide range of pulmonary function tests during treadmill exercise in dogs. Using this appliance, data were obtained from 6 normal dogs and 3 of the same dogs after left lung autotransplantation. All measurements were made during awake, resting conditions and again after 5-7 minutes of moderate exercise. Resting values for pulmonary function tests, hemodynamic parameters, blood gases and pH from both pulmonary and systemic arterial blood samples did not differ significantly between normal dogs and those studied after left lung autotransplantation. During treadmill exercise, cardiac output doubled and pulmonary vascular resistance decreased comparably in both groups of dogs. Heart rates in both groups rose to approximately 22 b/min and blood gases and pH remained normal. These results indicate the facemask/mouthpiece assembly permits normal ventilation during treadmill exercise. In addition, these data support the view that pulmonary auto transplantation per se need not impose obligatory defects in ventilatory and hemodynamic function despite the increased demands of treadmill exercise.

Inhibition of Peripheral Vascular Compensation after the Induction of Myocardial Ischemia in Dogs

The fact that peripheral vascular resistance fails to increase, or does so to only a small degree, thus contributing to hypotension after the onset of myocardial ischemia, has been noted in both clinical and experimental studies. We examined this phenomenon in canine kidney, mesentery, spleen, and skeletal muscle after occlusion via ligation of the circumflex coronary artery. Animals anesthetized with pentobarbital sodium (30 mg/kg, IV) and with intact vagus nerves exhibited reduced cardiac output (CO), maintenance of mean arterial blood pressure (MAP) at or near control levels, and increased total peripheral resistance (TPR). Blood flows to the kidney (RBF) and mesentery (MBF) were decreased resulting in substantial elevations of renal vascular resistance (RVR) and mesenteric vascular resistance (MVR). Blood flow supplied to the hindlimb skeletal muscle (FBF) by the femoral artery did not vary substantially from control levels and, therefore, neither did femoral vascular resistance (FVR). Splenic arterial blood flow (SpBF) was somewhat decreased but splenic vascular resistance (Sp VR) remained un changed. Heart rate exhibited no change from control levels. When coronary artery ligation was preceded by bilateral cervical vagot omy, CO was decreased as before but MAP exhibited sustained decreases. No change from control values was noted in RBF, FBF, MBF, or SpBF. RVR, MVR, and Sp VR were significantly decreased while FVR remained unchanged. TPR in all cases was increased but not to the same degree as was noted in nonvagotomized animals. Again, no change in heart rate occurred. Unlike the hemodynamic pattern observed in vagotomized dogs subjectedto the induction of myocardial ischemia, treatment of animals with a cholinergic blocking dose of atropine sulfate (1 mg/kg, IV) before coronary artery occlusion produced maintenance of MAP at or near control levels, lesser and slower reductions of CO and significantly increased TPR. No change was observed in RBF, FBF, MBF, SpBF or in RVR, FVR, MVR, and SpVR. Although there were no changes in heart rate from control levels, these values in atropinized dogs were usually higher than corresponding figures in other series. When the induction of mild pericardial tamponade was substituted for coronary artery ligation, both vagotomized and non-vagotomized dogs exhibited normal peripheral compensations to the resulting hypotension and CO reduction, i.e., RBF decreased markedly and RVR was substantially increased as was TPR. No change in heart rate occurred. These results indicate that (1) myocardial ischemia is necessary to trigger the abnormal loss of peripheral vascular compensatory responses; (2) vagal afferent nerves serve a protective function by mediating normal compensatory maneuvers, and (3) an additional mechanism, activated by ischemia but masked by the vagi, may cause inappropriate vasodilation when vagal afferent nerve activity is lost. A model has been constructed that presents a possible mechanism mediating the described phenomena.