Primary graft dysfunction is the predominant driver of mortality and graft loss after lung transplantation. Recruitment of neutrophils as a result of ischemia-reperfusion injury is thought to cause primary graft dysfunction; however, the mechanisms that regulate neutrophil influx into the injured lung are incompletely understood. We found that donor-derived intravascular nonclassical monocytes (NCMs) are retained in human and murine donor lungs used in transplantation and can be visualized at sites of endothelial injury after reperfusion. When NCMs in the donor lungs were depleted, either pharmacologically or genetically, neutrophil influx and lung graft injury were attenuated in both allogeneic and syngeneic models. Similar protection was observed when the patrolling function of donor NCMs was impaired by deletion of the fractalkine receptor CX3CR1. Unbiased transcriptomic profiling revealed up-regulation of MyD88 pathway genes and a key neutrophil chemoattractant, CXCL2, in donor-derived NCMs after reperfusion. Reconstitution of NCM-depleted donor lungs with wild-type but not MyD88-deficient NCMs rescued neutrophil migration. Donor NCMs, through MyD88 signaling, were responsible for CXCL2 production in the allograft and neutralization of CXCL2 attenuated neutrophil influx. These findings suggest that therapies to deplete or inhibit NCMs in donor lung might ameliorate primary graft dysfunction with minimal toxicity to the recipient.
Figure 1. Chest radiograph revealed a right hilar mass (A), which on contrast-enhanced computed tomography was found to be a large intravascular tumor occluding the right main pulmonary artery with extension into the lumen of the main and left pulmonary arteries (B). A dynamic magnetic resonance image demonstrated the tumor within the main pulmonary artery but without mural invasion (C). Tumor within the main pulmonary artery as visualized intraoperatively after pulmonary arteriotomy (D). Gross histology demonstrated involvement of superior, middle, and inferior lobes (E) with tumor completely occluding the right pulmonary artery lumen (F).
Figure 1. Evaluation of the middle lobe cavity. (A) Initial chest radiograph revealed a middle lobe cavity. (B) Chest computed tomography (CT) showed the large middle lobe cavity surrounded by the medial and lateral segmental bronchi. (C) Gross tissue analysis demonstrated an occlusive thrombus in the pulmonary artery branch to the middle lobe (black arrow). Histologic analysis revealed (D) organizing thrombus within the pulmonary artery showing signs of recanalization (43 magnification), and (E) diffuse alveolar damage with loss of architecture, septal thickening, and neutrophil infiltration (103 magnification). (F) New pulmonary emboli (green arrows) were found on CT angiogram performed after resection of the middle lobe.A 63-year-old male heart transplant recipient with recurrent lower extremity deep vein thrombosis, receiving warfarin, with chronically reduced glomerular filtration rate (30 ml/min), presented with worsening cough and dyspnea. Laboratory testing revealed normal blood cell counts, mildly elevated C-reactive protein, and international normalized ratio of 1.8. Subsequent radiograph revealed a middle lobe cavity ( Figure 1A). Bronchoalveolar fluid cultures revealed Candida albicans, but antifungal therapy cleared the organism after 2 weeks. Nevertheless, the cough persisted, and the cavity progressed over the following 6 weeks ( Figure 1B). Given the uncertain etiology of the cavity and persistence of symptoms, thoracoscopic middle lobectomy was performed, during which the majority of the lobe was found to be necrotic and filled with z10 ml of thick brown liquefied debris. Major and minor fissures were "complete," preventing any collateral blood supply to the middle lobe. Gross and histological examination revealed an occlusive thrombus in the pulmonary artery branch to the middle lobe. The majority of the lobar parenchyma had undergone necrosis, leading to the cavity formation, and the walls of the cavity adjacent to the minor and major fissures revealed microscopic features of alveolar A.B.
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