Flow-induced changes in vessel caliber tend to restore baseline wall shear stress (WSS) and have been reported to be endothelium-dependent. To investigate the role of endothelium-derived nitric oxide (NO) in the adaptive increase in artery diameter in response to a chronic increase in blood flow, an arteriovenous fistula was constructed between the left common carotid artery (CCA) and the external jugular vein in 22 New Zealand White rabbits, and NO synthesis was inhibited in 14 animals by long-term administration of NG-nitro-L-arginine-methyl ester (L-NAME) in drinking water given for 4 weeks. The remaining 8 animals served as controls. Mean arterial blood pressure was not significantly altered by L-NAME treatment (91 +/- 2 in control versus 98 +/- 3 mm Hg in L-NAME-treated rabbits). Blood flow significantly increased in the left CCA in both groups but was lower in L-NAME-treated than control animals (106.1 +/- 10.7 versus 196.2 +/- 32.3 mL/min, P < .003). The diameter of the flow-loaded left CCA also increased significantly in both groups compared with the right CCA (2.15 +/- 0.12 and 2.54 +/- 0.1 mm, respectively, P < .02), but the increase was less in the L-NAME-treated than the control group (3.24 +/- 0.09 and 4.64 +/- 0.17 mm, respectively, P < .0001). The diameter of the anastomosed veins was also increased but to a much lesser degree in L-NAME-treated animals than in controls (4.14 +/- 0.29 versus 7.94 +/- 0.51 mm, P < .0001). As a result of artery enlargement, WSS was normalized in the flow-loaded left CCA of the control group (8.87 +/- 0.77 dynes/cm2) regardless of blood flow values. In L-NAME-treated animals, however, WSS was only partially regulated, the mean value being significantly increased (18.7 +/- 2.2 dynes/cm2, P < .006). Moreover, a highly significant positive correlation between WSS and blood flow was obtained in L-NAME-treated animals (r = .84, P < .0001). We also found remodeling of the artery wall, with a larger increase in the medial cross-sectional area associated with an increased number of smooth muscle cells, in the control group compared with the L-NAME-treated group (0.75 +/- 0.09 versus 0.49 +/- 0.04 mm2 and 4504 +/- 722 versus 2717 +/- 282 cells/mm2, P < .03). We conclude that NO plays a role in the increase of vessel caliber in response to chronic increase in blood flow. As yet unidentified additional metabolic processes appear to be necessary for a complete regulatory response.

Abstract-Tears in the internal elastic lamina (IEL) can be observed after chronic increases in arterial blood flow, suggesting a potential role for matrix metalloproteinases (MMPs) in flow-induced vascular remodeling. We undertook to study this phenomenon by constructing an arteriovenous fistula (AVF) between the left common carotid artery (CCA) and the external jugular vein in rabbits. The diameter of the flow-loaded left CCA increased by 13.6Ϯ1.8% by day 3 after construction of the AVF compared with the right CCA (nϭ4, PϽ0.01) and by 40.7Ϯ7.5% by day-15 (nϭ10, PϽ0.0001). Increased CCA diameter also coincided with IEL fragmentation. Three days after construction of the AVF, gelatin zymography of protein extracts from left CCAs of untreated rabbits showed a significant increase in the 62-kDa (active MMP-2) activity and the appearance of a lytic band at 92 kDa (pro-MMP-9). In further experiments, MMP activity was inhibited by treatment with doxycycline (DOX) or BB-94, a specific MMP inhibitor. The increase in the 62-kDa gelatinolytic band was abolished in DOX-and BB-94 -treated rabbits. The 92-kDa gelatinolytic band was also reduced in DOX-treated animals. Furthermore, both increased left CCA diameter and IEL fragmentation were abolished in DOX-and BB-94 -treated rabbits. To evaluate whether nitric oxide was involved in blood flow-induced MMP activation, the rabbits were treated with N G -nitro-L-arginine methyl ester to inhibit nitric oxide synthesis. MMP activities were significantly decreased in the left CCAs of Key Words: wall shear stress Ⅲ vascular remodeling Ⅲ matrix metalloproteinases C hronic increases in arterial blood flow elicit an adaptive response of the arterial wall, characterized by the reorganization of cellular and extracellular components and leading to arterial enlargement and a reduction in wall shear stress (WSS) to physiological baseline values. [1][2][3][4] There is evidence that the endothelium plays an essential role in this adaptive process. 3,5 In models of arteriovenous fistula (AVF), endothelial denudation abolishes arterial diameter growth, 3 and we have shown that chronic inhibition of nitric oxide (NO) production by N G -nitro-L-arginine methyl ester (L-NAME) treatment inhibits, at least partially, the adaptive WSS regulation in flow-loaded vessels. 4 However, the mechanisms by which the endothelium or endothelium-dependent NO operates to induce arterial wall remodeling are not understood. Interestingly, disruption of the extracellular matrix with tears of the internal elastic lamina (IEL) can be observed in this model, which suggests a potential role for matrix metalloproteinases (MMPs) in matrix digestion and reorganization, leading to arterial wall remodeling, 4,6 -11 and for NO in MMP activation. 12 This study was therefore designed to examine the effects of chronic in vivo inhibition of MMPs by treatment with BB-94, a specific MMP inhibitor, or doxycycline (DOX), on vascular remodeling of the common carotid artery (CCA) in a rabbit model of AVF. We also evaluated the effect...

No abstract

Severe pulmonary hypertension is a common feature in patients with end-stage PLCH. Given the good postransplant survival rate and despite a recurrence rate of the disease of approximately 20% after LT, we conclude that LT is a therapeutic option in this setting.

To determine the usefulness of [18F]fluorodeoxyglucose (FDG) whole body FDG-PET in the diagnosis of tumours in patients with paraneoplastic neurological syndromes (PNS), we prospectively studied 20 patients with paraneoplastic antibodies in whom conventional imaging gave negative or inconclusive results for the presence of tumour. All 20 patients had neurological manifestations compatible with PNS and well-characterized paraneoplastic antibodies (12 anti-Hu, one anti-Hu and anti-CV2, one anti-CV2, four anti-Yo, one anti-Ri and one anti-amphiphysin). The mean delay between the onset of neurological symptoms and FDG-PET was 10 months (range 1-54). In these 20 patients, abnormal uptake was demonstrated in 18 patients, with some patients having abnormal signal in several areas. We observed abnormal uptake in the mediastinum (13 cases), lung (two cases), breast (two cases), parotid gland (one case), or the cervical, supraclavicular or axillary lymph nodes (seven cases). Following FDG-PET, the histological diagnosis of the tumour was made in 14 patients (small cell lung carcinoma in eight cases, breast adenocarcinoma in two, lung adenocarcinoma in two, axillary metastasis of ovary carcinoma in one, and malignant thymoma in one). Two other patients with abnormal FDG uptake showed radiological evidence of lung cancer, but a histological diagnosis could not be obtained. In two other patients, initial FDG-PET showed abnormal FDG uptake that was not confirmed a few months later by repeat FDG-PET. In the two patients with negative FDG-PET, peritoneal carcinomatosis was diagnosed in one and no tumour was found in the other. In our series, the sensitivity of FDG-PET for tumour detection was >83% demonstrating a clear role of this technique in the management of patients with PNS. However, in our series, the specificity of FDG uptake was only 25% due to unexplained abnormal FDG uptake in three patients and in abnormal FDG uptake due to a benign tumour in one patient. Over the study period, we saw 73 other patients with PNS and paraneoplastic antibodies. A tumour was demonstrated in 71 out of 73 by conventional techniques. Since false-positive and false-negative results are possible with FDG-PET and in most patients with PNS, the tumour is demonstrated by conventional techniques, we believe that FDG-PET should be reserved, at the moment, for patients with well-defined PNS antibodies when conventional imaging fails to identify a tumour or when lesions are difficult to biopsy.

Sleeve lobectomy is a safe and effective therapy for patients with resectable lung cancer. The presence of N1 and N2 disease, or of non-squamous carcinoma significantly worsen the prognosis.

Several risk factors for major adverse early outcomes after pneumonectomy for cancer were identified. Overweight patients and those who received induction therapy had paradoxically lower adjusted risks of mortality.

BackgroundHomeostatic turnover of the extracellular matrix conditions the structure and function of the healthy lung. In lung transplantation, long-term management remains limited by chronic lung allograft dysfunction, an umbrella term used for a heterogeneous entity ultimately associated with pathological airway and/or parenchyma remodeling.ObjectiveThis study assessed whether the local cross-talk between the pulmonary microbiota and host cells is a key determinant in the control of lower airway remodeling posttransplantation.MethodsMicrobiota DNA and host total RNA were isolated from 189 bronchoalveolar lavages obtained from 116 patients post lung transplantation. Expression of a set of 11 genes encoding either matrix components or factors involved in matrix synthesis or degradation (anabolic and catabolic remodeling, respectively) was quantified by real-time quantitative PCR. Microbiota composition was characterized using 16S ribosomal RNA gene sequencing and culture.ResultsWe identified 4 host gene expression profiles, among which catabolic remodeling, associated with high expression of metallopeptidase-7, -9, and -12, diverged from anabolic remodeling linked to maximal thrombospondin and platelet-derived growth factor D expression. While catabolic remodeling aligned with a microbiota dominated by proinflammatory bacteria (eg, Staphylococcus, Pseudomonas, and Corynebacterium), anabolic remodeling was linked to typical members of the healthy steady state (eg, Prevotella, Streptococcus, and Veillonella). Mechanistic assays provided direct evidence that these bacteria can impact host macrophage-fibroblast activation and matrix deposition.ConclusionsHost-microbes interplay potentially determines remodeling activities in the transplanted lung, highlighting new therapeutic opportunities to ultimately improve long-term lung transplant outcome.