A Critical Role for Airway Microvessels in Lung Transplantation

Lung transplantation permits a lifesaving treatment for patients with terminal pulmonary vascular and parenchymal diseases. As blood vessels, lymphatics, and nerves are severed and incompletely restored at the time of transplantation, these anatomic derangements may contribute to early- and late-arising pathologies. Experimental and clinical evidence is mounting that microvessel damage, in particular, is bad for solid organ allografts, such as lung transplants.

In this issue of the Journal, Kraft and colleagues (pp. 552–560) build on prior observations that airways in transplanted lungs are hypoxic at baseline because the bronchial artery circulation is not restored at the time of surgery (1). The Duke investigators confirmed findings made in the original Stanford study (2) that donor tissue oxygen saturations are reduced in airways; they significantly extend these findings by showing that hypoxia-inducible genes are up-regulated in donor lungs and are associated with airway necrosis, central airway stenosis, and worse clinical outcomes. The authors also note a relationship between up-regulation of hypoxic genes in transplanted airways with prolonged respiratory failure and prolonged hospitalization; however, these latter results could be dependent on factors more important than airway hypoxia, making these findings harder to attribute to a missing bronchial artery circulation.

Anatomy and Fate of Airway Microvasculature after Lung Transplantation

The bronchial arteries carry highly oxygenated blood to supply the bronchial mucosa as well as the visceral pleura. The bronchial circulation is not routinely reanastomosed at the time of transplantation. As indicated by the Duke and Stanford studies, loss of this native circulation renders airways relatively hypoxic after transplantation and dependent on blood originating from the pulmonary circulation, emerging collateral vessels, and ambient air.

Optimization of surgical techniques has significantly limited central airway complications, such as stenosis and dehiscence, but the current study raises the concern that despite these refinements, transplanted airways are compromised because of an altered microcirculation. Beyond creating a predisposition for large airway complications, as suggested by the current study, the later loss of airway microvasculature resulting from alloimmune rejection may be an important reason for developing the bronchiolitis obliterans syndrome (BOS).

An autopsy study demonstrated a significant dropout of microvasculature in pre-BOS airways contiguous with BOS airways, suggesting that microvascular loss and airway ischemia is a preceding condition to airway fibrosis (3). As noted, the late dropout of microvessels in pre-BOS airways could be a result of immune-mediated injury. On the heels of this discovery, it has been reported that the loss of the airway microcirculation identified those airway grafts that could not be rescued from fibrosis with immunotherapy (4). This preclinical study suggested that steroid resistance in chronic rejection may be attributable, in part, to the destruction of the microvasculature in grafts. In summary, a compromised microcirculation resulting from missing bronchial arterial blood flow at the time of transplantation appears to have clinical importance for central airway health, whereas alloimmune-mediated microvascular attrition may significantly contribute to chronic rejection. The graft microenvironment appears to have a strong effect on the development of chronic allograft dysfunction. Not only does alloimmune inflammation lead to the destruction of microvessels and regions of hypoxic tissue beds, but it is also likely that the resulting tissue ischemia fosters dysregulated angiogenesis and abnormal blood flow (5, 6).

Nonvascular Consequences of Surgical Lung Implantation

Beyond loss of the bronchial artery circulation, the transplanted lung must also endure a disruption of its native lymphatics and neural supply; the implications of these deficits remain poorly understood. A new study by Cui and colleagues addresses how the complete interruption of lymphatic flow may worsen lung transplant outcomes (7). Studies on the disrupted neural supply in lung transplantation, chiefly of the branches afferent to the vagus nerve from the lung, are few and not updated. These branches wire impulses from the lung to the brain, mostly from the neuroepithelial bodies that analyze the hypoxic environment or the inflation status of the lung parenchyma with the smooth muscle-associated airway receptors (8). The inflation inhibitory reflex is greatly reduced in lung transplant patients, and vagal denervation increases breathing pattern variability (9). Lymphatic and neural interruption appear to be an important area of future transplant research.

Strategies to Improve Lung Allograft Function

Bronchial Artery Revascularization

Several studies by Gösta Pettersson’s group have demonstrated that this operation can be feasible and beneficial. A single-center experience of en bloc double-lung transplants with bronchial artery revascularization (BAR) performed by Pettersson’s Copenhagen group in the 1990s showed excellent success and long-term survival relative to a more recent series of sequential bilateral non-BAR lung transplants from the same institution (10, 11). As might have been predicted by the current article by Kraft and colleagues, a follow-up study at the Cleveland Clinic demonstrated that BAR limited central airway ischemia and anastomotic complications (12). A Norwegian study showed by endoscopic laser Doppler flowmetry that BAR improved airway perfusion (13). However, any putative benefits gained by BAR may be offset by unacceptable risks. Most BAR operations are performed with both lungs explanted as a single unit (i.e., en bloc) in a process described as cumbersome and that adds to an already lengthy operation (14). Refined surgical techniques have significantly diminished the incidence of anastomotic complications and, in so doing, remove one of the major reasons for performing the revascularization procedure (15). Nevertheless, the issue of vascular compromise remains an open one, and the Duke study in this issue of the Journal raises again the question of what can be safely done to optimize transplant health.

Ex Vivo Lung Perfusion Reconditioning

The donor lung management using ex vivo lung perfusion systems could potentially prevent collapse of microvasculature during preservation and decrease cold ischemia-related damage (16). In addition, dual ex vivo lung perfusion using both pulmonary and bronchial artery perfusion has been shown to increase microvasculature and perfusion compared with organs maintained on standard ex vivo lung perfusion. This resulted in better posttransplant outcomes in an experimental model (17).

Other Medical Therapies

As suggested by the authors, application of intermittent hyperbaric oxygen therapy in a posttransplant period may improve airway healing and reduce anastomotic complications (18, 19). The promotion of therapeutic lymphangiogenesis and airway microvascular regeneration are other promising strategies that might improve post-lung transplant outcomes (6, 7, 20).

Summary and Future Directions

Since its inception, the field of solid organ transplantation has focused, with good reason, on limiting destructive alloimmune responses. However, not withstanding immunity issues, increasing attention is now being given to how the actual anatomy of the intragraft microenvironment influences short- and long-term airway health.

Although there is ongoing disagreement about the merits of performing BAR, several things are clear: even if BAR were routinely performed, the airway microcirculation would remain vulnerable to alloimmune injury and the lymphatic circulation and airway neural system would still remain disrupted. Medical strategies that can promote vascular, lymphatic, and neural regrowth is a promising approach that can be undertaken as the BAR question is resolved by the transplant community (6, 7, 20). The Kraft study (1) is an important step forward in advancing the argument that additional steps can and should be taken at the time of lung transplantation to restore transplant anatomy and physiology.