Citations

Circulating leukocytes activated during rejection of organ allografts could potentially have generalized effects on systemic blood vessels of the transplant recipient. Experiments were designed, therefore, to determine the function of the endothelium and smooth muscle of arteries from nontransplanted organs in dogs who received single lung transplants. Dogs underwent single lung allotransplantation and were immunosuppressed for 5 days. Immunosuppression was then withheld for 3 days, allowing rejection to occur. Dogs were studied at this time (rejecting) or following treatment for rejection for an additional 6-8 days (treated). Arteries from unoperated, untreated dogs also were studied to provide baseline responses of healthy tissue. Rings cut from left circumflex coronary, nonoperated native pulmonary, and renal arteries were suspended in organ chambers for measurement of isometric force. Endothelium-dependent relaxations to the calcium ionophore A23187 were not affected by rejection in any of the arteries. Contractions to angiotensin I were reduced significantly only in native pulmonary arteries. Contractions to KCI and endothelin-1 increased in renal arteries with endothelium during rejection. These contractions in renal arteries were reduced following treatment of rejection. None of the responses of the coronary arteries were affected significantly by rejection of the lung allograft. These results demonstrate that contractions of arteries in the transplant recipient's native organs are altered during rejection of lung allografts. The effects are organ specific, may include production of endothelium-derived contractile factors in renal arteries, and can be partially reversed by treatment of rejection.

Lungs allografts have worse long-term survival compared with other organ transplants. This is most likely due to their unique immunoregulation that may not respond to traditional immunosuppression. For example, local NO generation by inducible NOS (iNOS) is critical for lung allograft acceptance but associates with rejection of other solid organs. The source of NO in accepting lung allografts remains unknown. Here, we report that, unlike the case for other pulmonary processes in which myeloid cells control NO generation, recipient-derived eosinophils play a critical and nonredundant role in iNOS-mediated lung allograft acceptance. Depletion of eosinophils reduces NO levels to that of recipients with global deletion of iNOS and leads to a costimulatory blockade–resistant form of rejection. Furthermore, NO production by eosinophils depends on Th1 polarization by inflammatory mediators, such as IFN-γ and TNF-α. Neutralization of such mediators abrogates eosinophil suppressive capacity. Our data point to what we believe to be a unique and previously unrecognized role of eosinophil polarization in mediating allograft tolerance and put into perspective the use of high-dose eosinophil-ablating corticosteroids after lung transplantation.

The scaffold protein synectin plays a critical role in the trafficking and regulation of membrane receptor pathways. As platelet-derived growth factor receptor (PDGFR) is essential for hepatic stellate cell (HSC) activation and liver fibrosis, we sought to determine the role of synectin on the PDGFR pathway and development of liver fibrosis. Mice with deletion of synectin from HSC were found to be protected from liver fibrosis. mRNA sequencing revealed that knockdown of synectin in HSC demonstrated reductions in the fibrosis pathway of genes, including PDGFR-β. Chromatin IP assay of the PDGFR-β promoter upon synectin knockdown revealed a pattern of histone marks associated with decreased transcription, dependent on p300 histone acetyltransferase. Synectin knockdown was found to downregulate PDGFR-α protein levels, as well, but through an alternative mechanism: protection from autophagic degradation. Site-directed mutagenesis revealed that ubiquitination of specific PDGFR-α lysine residues was responsible for its autophagic degradation. Furthermore, functional studies showed decreased PDGF-dependent migration and proliferation of HSC after synectin knockdown. Finally, human cirrhotic livers demonstrated increased synectin protein levels. This work provides insight into differential transcriptional and posttranslational mechanisms of synectin regulation of PDGFRs, which are critical to fibrogenesis.

Background Nonpulsatile pulmonary blood flow in Fontan circulation results in pulmonary vascular disease, but the potential relationships between pulmonary vascular resistance index (PVRI) and Fontan failure have not been studied. The objective was to determine whether the absence of subpulmonary ventricle in the Fontan circulation would make patients more vulnerable to even low-level elevations in PVRI, and when coupled with low cardiac index, this would identify patients at increased risk of Fontan failure. Methods and Results Two hundred sixty-one adult Fontan patients underwent cardiac catheterization; age 26±3 years, men 146 (56%), atriopulmonary Fontan 144 (55%). Patients were divided into 2 groups: those with high PVRI (>2 WU·m 2 ) and low cardiac index <2.5 L min −1 m −2 (group 1, n=70, 30%), and those with normal PVRI and normal cardiac index (group 2, n=182, 70%). Fontan failure was defined by the composite of all-cause mortality, listing for heart transplantation, or initiation of palliative care. There were 68 (26%) cases of Fontan failure during a mean follow-up of 8.6±2.4 years. When compared with group 2, freedom from Fontan failure was significantly lower in group 1: 66% versus 89% at 5 years. The combination of high PVRI and low cardiac index was an independent risk factor for Fontan failure (hazard ratio, 1.84; 95% confidence interval, 1.09–2.85). Conclusions When coupled with low cardiac index, even mild elevations in PVRI identify patients at high risk of Fontan failure. This suggests that pulmonary vascular disease is a key mechanism underlying Fontan failure and supports further studies to understand the pathophysiology and target treatments to pulmonary vascular tone in this population.

Development of late-onset respiratory diseases is associated with elevated 8-isoprostane, a marker of oxidative stress, in the airways. However, sex differences exist in development of these diseases. Using an exhaustive exercise bout as a physiological stressor may elucidate whether there is a sex difference with aging in pre- to postexercise airway 8-isoprostane generation. The purpose of this study was to determine whether older women exhibit a greater airway 8-isoprostane response to exhaustive exercise compared with older men and younger controls. Thirty-six individuals completed the study (12 postmenopausal older women (OW) and 12 age-matched older men (OM), 65 ± 4 years of age; and 12 younger controls (YC), 21 ± 2 years of age). Baseline measurements included exhaled breath condensate (EBC) for assessment of airway 8-isoprostane and standard pulmonary function tests (PFTs) to assess forced expiratory volume in 1-s (FEV1), forced vital capacity (FVC), FEV1/FVC, and forced expiratory flow at 25%–75% of FVC. Subjects then performed a peak oxygen uptake test to exhaustion on a cycle ergometer. Immediately postexercise, PFTs and EBC were performed. The generation of airway 8-isoprostane from pre- to postexercise was greater in OW compared with OM and YC (p < 0.01), increasing ∼74% ± 77% in OW, while decreasing in OM (∼12% ± 50%) and YC (∼20.9% ± 30%). The OW exhibited a greater airway 8-isoprostane response to exhaustive exercise compared with OM and YC, which may suggest that sex differences in oxidative stress generation following exhaustive exercise may provide a mechanistic rationale for sex differences in late-onset respiratory diseases.

OBJECTIVEReconstructive options for brachial plexus lesions continue to expand and improve. The purpose of this study was to evaluate the prevalence and quality of restored elbow extension in patients with brachial plexus injuries who underwent transfer of the spinal accessory nerve to the motor branch of the radial nerve to the long head of the triceps muscle with an intervening autologous nerve graft and to identify patient and injury factors that influence functional triceps outcome.METHODSA total of 42 patients were included in this retrospective review. All patients underwent transfer of the spinal accessory nerve to the motor branch of the radial nerve to the long head of the triceps muscle as part of their reconstruction plan after brachial plexus injury. The primary outcome was elbow extension strength according to the modified Medical Research Council muscle grading scale, and signs of triceps muscle recovery were recorded using electromyography.RESULTSWhen evaluating the entire study population (follow-up range 12–45 months, mean 24.3 months), 52.4% of patients achieved meaningful recovery. More specifically, 45.2% reached Grade 0 or 1 recovery, 19.1% obtained Grade 2, and 35.7% improved to Grade 3 or better. The presence of a vascular injury impaired functional outcome. In the subgroup with a minimum follow-up of 20 months (n = 26), meaningful recovery was obtained by 69.5%. In this subgroup, 7.7% had no recovery (Grade 0), 19.2% had recovery to Grade 1, and 23.1% had recovery to Grade 2. Grade 3 or better was reached by 50% of patients, of whom 34.5% obtained Grade 4 elbow extension.CONCLUSIONSTransfer of the spinal accessory nerve to the radial nerve branch to the long head of the triceps muscle with an interposition nerve graft is an adequate option for restoration of elbow extension, despite the relatively long time required for reinnervation. The presence of vascular injury impairs functional recovery of the triceps muscle, and the use of shorter nerve grafts is recommended when and if possible.

Brain mutations, young and old Most neurons that make up the human brain are postmitotic, living and functioning for a very long time without renewal (see the Perspective by Lee). Bae et al. examined the genomes of single neurons from the prenatal developing human brain. Both the type of mutation and the rates of accumulation changed between gastrulation and neurogenesis. These early mutations could be generating useful neuronal diversity or could predispose individuals to later dysfunction. Lodato et al. also found that neurons take on somatic mutations as they age by sequencing single neurons from subjects aged 4 months to 82 years. Somatic mutations accumulated with increasing age and accumulated faster in individuals affected by inborn errors in DNA repair. Postmitotic mutations might only affect one neuron, but the accumulated divergence of genomes across the brain could affect function. Science , this issue p. 550 , p. 555 ; see also p. 521