Functional Neural Regeneration after Pulmonary Denervation

Functional Neural Regenerati on after Pulmonary Denervation*

George E. Duooisin, M.D.; W. Spencer Payne, M.D., F.G.G.P.; F. Henry Ellis, t-; "AJ.D.; and Ward S. Fotvler, M.D.

Reimplantation of the lung produces complete interruption of all ipsilateral pulmonary nerves. A consequence of this denervation is the loss of the pulmonary stretch-receptor (Hering-Breuer) reflex. Forty-four dogs were studied for stretch-receptor activity one day to 17 months after unilateral orthotopic pulmonary reimplantation. Stretch-receptor activity was observed to return in five of the reimplanted lungs 9 to 12 months after operation, establishing that functional neural regeneration can occur after pulmonary denervation.

R eimpluntation of the lung produces unequivocal

pressure in the presence of intact innervation, the respiratory rate can be slowed markedly, even to the point of apnea. The use of a divided airway and spirometer permitted the selective increase of intrabronchial and transpulmonary pressure in each lung. By applying known weights to the appropriate spirometer bell, positive intrabronchial pressures, ranging from 3 to 14 Clll of water, were produced. The response to increased intrabronchial pressure was recorded on the spirometric tracing of the contralateral lung (Fig 1 ) .

pulmonary denervation. Recent reports state that there is no anatomic evidence of neural regeneration.! The purpose of this report is to describe our method of testing functional stretch-receptor activity and to document both disappearance and return of functional vagal activity following denervation of the lung.

RESULTS

~IETHODS

Increased transpulmonary pressure in each lung produced marked slowing of the respiratory rate to apnea in all 20 preoperative control animals (Table ). After denervation of the left lung by reimplantation, each lung was tested separately one or more times on 118 technically satisfactory spirometric tracings in the 44 animals at intervals ranging from one day to 17 months after operation. The normally innervated right lung consistently responded to the increased pressure with normal slowing or apnea in alll18 tracings. None of the 44 animals showed any evidence of stretch-receptor activity in the denervated left lung up to nine months after operation, that is, the respiratory rate did not slow when the transpulmonary pressure was increased in the denervated lung. In 39 of the 44 animals, this response persisted up to 16 months after reimplantation irrespective of the presence or absence of structural defects or

The left lung was denervated by reimplantation in 44 dogs, through use of methods described previously.P Spirometry was performed before and at intervals from one day to ] 7 months after operation to assess pulmonary Function'! and to test the status of vagal innervation." Simultaneous tidal volume and oxygen uptake of each lung were measured by means of a Wright-Lategola divided airway and a Collins twin spirometer. All examinations were performed under general anesthesia induced with pentobarbital given intravenously and with the animul supine. The stretch-receptor response test employed is based on the Hering-Breuer reflex as follo\vs: Slowly adapting receptors': of the tracheobronchial tree are stretched by distention, increasing the number of impulses transmitted over the afferent vagal fibers'"7 which inhibit the initiation of further inspiratory activity by the respiratory center. By increasing the transpulmonary o FrOIH

the Muyo Clinic and Mayo Foundation: Section of Surgery (Drs. Duvoisin, Payne, and Ellis) and of Physiology (n-. Fowler I, Hochester, Minnesota. This investigation was supported in part by Research Grant HE-3,~HH from the National Institutes of Health, Public Health Service, and by a grant from the Minnesota Heart Association.

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FUNCTIONAL NEURAL REGENERATION I' minute I

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FIGURE 1. Spirometric demonstration of stretch-receptor response of normally innervated right lung and denervated (reimplanted ) left lung. Tracings read from right to left, with inspiration recorded by an upward stroke. Increase of intrahronchial pressure (at "Inflate") of left denervated lung failed to evoke any change in rate of respiration as displayed in tracing for right lung immediately above. Tidal-volume changes of inflated lung are attenuated by loading of spirometer bell, which also displaces water from housing and exaggerates apparent pulmonary inflation. A normal response, however, is demonstrated with increase of intrabronchial pressure (at "Inflate") of right normally innervated lung as displayed in spirometric tracing of left lung immediately below. This shows complete apnea of stretch-receptor stimulation. (Spirometric tracing of a IS-kg dog with good bilateral ventilation and oxygen uptake three months after reimplantation of left lunz.}

ventilatory function in the reimplanted lung. The remaining five dogs showed no vagal activity during the first nine months after reimplantation, but a return of stretch-receptor response was documented at postoperative intervals of nine months (three dogs), ten months (one dog), and 12 months (one dog) (Table). In these animals the first sign of returning stretch-receptor activity was an indefinite slowing response to a pressure of 14 em of water, In the ensuing six to eight weeks, definite slowing of the respiratory rate with successively lower pressures was observed until onlv 3 cm of water pressure was required to elicit a definite slowing response. The return of stretch-receptor response was not dependent on return of normal oxygen uptake and ventilation in the reimplanted lung. Neither tidal volume nor frequency of respiraStretch-Receptor Activity St retch-Receptor Act ivit y Present

Test Dogs Tracings

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CHEST, VOL. 58, NO.5, NOVEMBER 1970

tion was altered by unilateral denervation and, of course, neither changed with reinnervation. CO~[~[ENT

Pulmonary innervation has played a prominent role in the interpretation of the functional results of reimplantation of the lung. Diminished pulmonary function and failure to survive contralateral pneumonectomy have both been attributed to the denervated status. Previous reports from our laboratory" and those of others":" have established not only that the completely denervated lung is capable of supporting the respiratory requirements of the labratory animal but also that complete pulmonary denervation is compatible with spontaneous respiration and long-term survival. Thus while vagal nerves have an effect upon the control of respiration, this function does not appear to be essential to spontaneous respiration or survival. A few reports 1 o, 1 1 have assessed the long-term physiologic neural status after reimplantation. \Vhile anatomic and histologic studies 1 have not demonstrated regeneration, they do not reflect the functional aspect. Trummer and Berg 11 have demonstrated return of the stretch-receptor response as early as seven months after reimplantation. It is apparent from their observations and ours that if reinnervation has not occurred by one year it is not likely to occur subsequently.

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YASUMURA, FOWLER AND PAYNE REFERENCES

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Nigro SL, Hirsch EF, Hams Il. et al: Regression of the intrinsic nerves and other sequelae with reimplantation of the lung. J Thorne Cardiovasc Surg .54:81.5, IB67 Duvoisin C;E, Payne \VS, Ellis FlI Jr: Influence of surgical technique on the results of pulmonary reimplantation, Chest 58:B6, IB70 Duvoisin GE, Fowler \~'S, Ellis FH j-, et al: Causes of depressed pulmonary function following reimplantation of the canine lung. Chest 58: 102, 1970 Duvoisin GE, Fowler WS, Payne \VS, et al: Reimplantation of the dog lung with survival after contralateral pneumonectomy, Surg Forum 15: 173, 1964 Widdicombe JC;: Hespiratory reHexes in man and other mammalian species. Clin Sci 21 : 163, 1961 Adrian ED: Afferent impulses in the vagus and their effect on respiration. J Physiol (London) 79: 332, 1933

7 Davis HL, Fowler \VS, Lambert EH: Effect of volume and rate of inflation and deflation on transpultnonary pressure and response of pulmonary stretch receptors. Amer .1 Physiol 187: .5.58, 19.56 8 Faber LP, Pcdreiru ALS, Pevsner PH, et al: The imnu-diate and long-term physiological function of bilateral reimplanted lungs. J Thorac Cardiovasc Surg .50:7fil, IB6.5 9 Sliin ~IS, Yacouhiun HD, \Vilson JL, et al: Successful hilateral reimplantation of canine lungs. Sn rgery 55: 670, 1964 10 ~Iarshall H, Cunniru; AJ: The long-term physiological effects of lung reimplantation in the dog. J Surg Hes 6: 185, 1966 11 Trummer ~1.1, Berg P: Lung Transplantation, Springfield, Illinois, Charles C Thomas, Publisher, 1BBS, p .57 Reprint requests: Section of Publications, Mayo Clinic. Rochester, Minnesota 55901.

Variation in Ventilation and Inspired-gas Composition during Pulmonary Artery Occlusion of the Hilar-stripped Lung: Effects on Subsequent Pulmonary Function* Yutaka Yasumura, A/.D., "'ard S. Eoicler, l\f.D., and

\\1. Spencer Payne, A/.D., F.G.G.P.

Ventilatory maneuvers during two hours of pulmonary artery occlusion in the hilar-stripped lung did little to accentuate or ameliorate depression of subsequent pulmonary function. Avoidance of complete collapse of the lung seemed more important to early function than did oxygen content of the inflating gas. The presence or absence of carbon dioxide in the ventilating gas did not clearly affect subsequent pulmonary function after pulmonary artery occlusion and hilar stripping. Bronchial artery interruption accompanying hilar stripping without bronchial division was associated with a heretofore unrecognized high incidence of distal bronchial ischemic injury. It is concluded that factors other than hilar stripping and temporary interruption of pulmonary artery flow should be sought to explain the early dysfunction following successful reimplantation of the lung.

A side from

failure of allogenic lung transplants for immunologic reasons, certain functional derangements appear to result from division or reanastomosis of hilar structures. Studies of the reimplanted dog lung l - 4 indicate that the procedure severely depresses ventilation, perfusion, and oxygen uptake by the lung for two to six weeks. °From the Mayo Clinic and Mayo Foundation: Section of Physiology (Dr. Fowler) and of Surgery (Dr. Payne). Mayo Graduate School of Medicine (University of Minnesota}, Rochester: Resident in Surgery (Dr. Yasurnura ). This investigation was supported in part by a research grant from the Minnesota Respiratory Health Association and by Research Grant HE-3.588 from the National Institutes of Health, Public Health Service.

Various factors, including technical complications,1.5.6 denervation,":" and ischemia, 1 0.11 have been implicated in the genesis of these dysfunctions Following reimplantation of the lung. However, there is evidence that the type of ventilation and oxygen tension of respired gases used to ventilate excised, non perfused lungs affect their mechanical properties and surfactant activity of extracts from them.I s Also, complete collapse of lungs with ligation of the pulmonary artery is accompanied by greater edema and hemorrhage than when ventilation or inflation is rnaintained.J " Previous studies dealing with the effects of the division of individual CHEST, VOL. 58, NO.5, NOVEMBER 1970