Altered lymphocyte trafficking and diminished airway reactivity in transgenic mice expressing human MMP-9 in a mouse model of asthma.

Matrix metalloproteinase-9 (MMP-9) is hypothesized to facilitate leukocyte extravasation and extracellular remodeling in asthmatic airways. Careful descriptive studies have shown that MMP-9 levels are higher in the sputum of asthmatics; however, the consequence of increased MMP-9 activity has not been determined in this disease. We induced asthma in transgenic mice that express human MMP-9 in the murine lung tissue macrophage to determine the direct effect of human MMP-9 expression on airway inflammation. Transgenic (TG) and wild-type (WT) mice were immunized and challenged with ovalbumin. Forty-eight hours after the ovalbumin challenge, airway hyperresponsiveness (AHR) was measured, and inflammatory cell infiltration was evaluated in bronchoalveolar lavage fluid (BALF) and lung tissue. Baseline levels of inflammation were similar in the TG and WT groups of mice, and pulmonary eosinophilia was established in both groups by sensitization and challenge with ovalbumin. There was a significant reduction in AHR in sensitized and challenged trangenics compared with WT controls. Although total BALF cell counts were similar in both groups, the lymphocyte number in the lavage of the TG group was significantly diminished compared with the WT group (0.25 +/- 0.08 vs. 0.89 +/- 0.53; P = 0.0032). In addition, the draining lymphocytes were found to be larger in the TG animals compared with the WT mice. Equal numbers of macrophages, eosinophils, and neutrophils were seen in both groups. IL-13 levels were found to be lower in the sensitized TG compared with the WT mice. These results demonstrate an inverse relationship between human MMP-9 and AHR and suggest that MMP-9 expression alters leukocyte extravasation by reducing lymphocyte accumulation in the walls of asthmatic airways.

Blockade of receptor for advanced glycation end product attenuates pulmonary reperfusion injury in mice.

OBJECTIVE: The receptor for advanced glycation end products (RAGE) is expressed at high levels in the lung, particularly in type 1 alveolar cells, and has been shown to amplify injury triggered by acute stress. Previous studies suggest serum concentrations of soluble RAGE increase during pulmonary reperfusion injury after transplantation. RAGE blockade has been shown to suppress hepatic and cardiac ischemia and reperfusion injury in mice. Thus we tested the hypothesis that RAGE mediates tissue-injury mechanisms in ischemia and reperfusion injury in the lung. METHODS: C57BL/6 mice were subjected to 30 minutes of pulmonary ischemia by clamping the left hilum, followed by 60 minutes of reperfusion. Lung function was assessed by means of blood gas analysis, and capillary leak was assessed by injecting fluorescein isothiocyanate-labeled albumin and comparing fluorescence in bronchial lavage fluid with that in serum. Histologic analysis of the lung was performed by a pathologist naive to the experimental conditions. RESULTS: In animals subjected to RAGE blockade, significant increases in Po(2) (108 vs 73 mm Hg, P = .0094) and more than 3-fold decrease in capillary leak Relative Fluorescent Units (RFU, 6.12 vs 1.75; P = .001) were observed. Histologic examination revealed significant injury reduction in soluble RAGE-treated animals versus control animals. RAGE knockout mice exhibited a protected phenotype when exposed to pulmonary ischemia and reperfusion. Additionally, interleukin 8 production and nuclear factor kappaB activation were increased in control mice. CONCLUSION: Abrogation of RAGE signaling attenuates pulmonary ischemia and reperfusion injury. This study suggests that RAGE might play a central role in pulmonary reperfusion injury and in transplantation and that blockade of RAGE might offer a potential target to abrogate pulmonary reperfusion injury in clinical transplantation.

Platelet activation in the postoperative period after lung transplantation.

OBJECTIVE: During lung transplantation, cells in the pulmonary parenchyma are subjected to ischemia, hypothermic storage, and reperfusion injury. Platelets, whose granular contents include adhesion receptors, chemokines, and coactivating substances that activate inflammatory and coagulant cascades, likely play a critical role in the lung allograft response to ischemia and reperfusion. The platelet response to the pulmonary allograft, however, has never been studied. Here we report significant platelet activation immediately after lung transplantation. METHODS: We performed a prospective cohort study comparing markers of platelet activation in patients undergoing lung transplantation and patients undergoing nontransplant thoracotomy. Plasma levels of soluble P-selectin, soluble CD40 ligand, and platelet-leukocyte conjugates were measured before surgery, after skin closure, and at 6 postoperative hours. RESULTS: Both soluble P-selectin and soluble CD40 ligand levels increased significantly after lung transplantation but not after thoracotomy. Additionally, platelet-monocyte conjugate fluorescence was significantly higher after lung transplantation than after thoracotomy alone. CONCLUSION: These findings suggest that platelet activation is significantly increased after lung transplantation beyond that expected from the postoperative state. The increase in circulating platelet-monocyte conjugates suggests an important interaction between platelets and inflammatory cells. Further research should examine whether platelet activation affects early graft function after lung transplantation.

Postlung transplant survival is equivalent regardless of cytomegalovirus match status.

BACKGROUND: The purpose of this study was to assess (1) the relationship between donor-recipient cytomegalovirus (CMV) serologic status and posttransplant survival in the current era and (2) temporal changes in posttransplant survival by CMV matching status. METHODS: De-identified data were obtained from the United Network for Organ Sharing. Based on pretransplant CMV serologic status (+ or -) of recipients (R) and donors (D), posttransplant survival was compared among three groups: D+ /R-, D+/- /R+, and D- /R-. Primary analysis focused on transplants performed January 1, 2000 to December 31, 2004, in recipients 18 years of age or older. To assess temporal trends in survival among groups, all lung transplants occurring between January 1, 1990, and December 31, 2004, were considered and divided into three periods based on transplant year: 1990 through 1994, 1995 through 1999, and 2000 through 2004. The primary outcome measure was survival, reported as rate of death per 100 patient-years. Kaplan-Meier analysis with log-rank test was used for time-to-event analysis. RESULTS: During the current era (2000 through 2004), D+ /R- (n = 951), D+/- /R+ (n = 2,676), and D- /R- (n = 772) exhibited no differences in survival (p = 0.561), with rates of death per 100 patient-years of 16.6 (95% confidence interval, 14.9 to 18.5), 15.0 (95% confidence interval, 14.0 to 16.0), and 14.7 (95% confidence interval, 13.0 to 16.6), respectively. However, survival was significantly different for groups in the earlier eras of 1990 through 1994 (p < 0.001) and 1995 through 1999 (p < 0.001). During the three periods, survival improved significantly in D+ /R- (p < 0.001) and D+/- /R+ (p < 0.001), but survival in D- /R- (p = 0.351) did not change significantly with time. CONCLUSIONS: In the current era, survival after lung transplantation is statistically equivalent regardless of CMV match status. Although in previous eras survival was worse among the D+/- /R+ and D+ /R- groups, in this era of aggressive CMV prophylaxis, CMV mismatch should not be sufficient grounds to decline a lung allograft offer.

Surgical therapy of lung metastases.

Almost 125 years after the first documented case, pulmonary metastasectomy is still poorly understood. No other organ is subject to the wide histologic variety of metastatic insults, and this fact has complicated a complete exposition of when pulmonary metastasectomy may be beneficial. Many physicians still consider pulmonary metastatic disease to be always incurable, and they may underestimate existing surgical options including the benefits of pulmonary metastasectomy. In addition, technological improvements in radiological screening of pulmonary metastases and thoracoscopic resection are fundamentally altering the management of these patients and their surgery. This article reviews the history, form, and future of pulmonary metastasectomy, the literature that supports or refutes its application in various tumor types, and the screening and surgical evaluation that is needed prior to its performance.

Treatment of bronchomalacia in cystic fibrosis by silicone stent.

We report the case of a 15-year-old girl with cystic fibrosis and rapidly declining pulmonary function tests who was found to have collapse of the left main bronchus from bronchomalacia. She underwent successful deployment of an expandable silicone stent in the collapsed bronchus, after which her pulmonary function test results and her clinical picture markedly improved, obviating the need for immediate transplantation. A literature review yielded no prior reports of bronchomalacia in a cystic fibrosis patient being treated with a silicone stent. This case shows that a simple, effective treatment is possible for one cause of obstructive pulmonary function in cystic fibrosis.