No abstract

Nowak K, Weih S, Metzger R, Albrecht II RF, Post S, Hohenberger P, Gebhard MM, Danilov SM. Immunotargeting of catalase to lung endothelium via anti-angiotensin-converting enzyme antibodies attenuates ischemia-reperfusion injury of the lung in vivo. Am J Physiol Lung Cell Mol Physiol 293: L162-L169, 2007. First published April 13, 2007 doi:10.1152/ajplung.00001.2007.-Limitation of reactive oxygen species-mediated ischemia-reperfusion (I/R) injury of the lung by vascular immunotargeting of antioxidative enzymes has the potential to become a promising modality for extension of the viability of banked transplantation tissue. The preferential expression of angiotensin-converting enzyme (ACE) in pulmonary capillaries makes it an ideal target for therapy directed toward the pulmonary endothelium. Conjugates of ACE monoclonal antibody (MAb) 9B9 with catalase (9B9-CAT) have been evaluated in vivo for limitation of lung I/R injury in rats. Ischemia of the right lung was induced for 60 min followed by 120 min of reperfusion. Sham-operated animals (sham, n ϭ 6) were compared with ischemia-reperfused untreated animals (I/R, n ϭ 6), I/R animals treated with biotinylated catalase (CAT, n ϭ 6), and I/R rats treated with the conjugates (9B9-CAT, n ϭ 6). The 9B9-CAT accumulation in the pulmonary endothelium of injured lungs was elucidated immunohistochemically. Arterial oxygenation during reperfusion was significantly higher in 9B9-CAT (221 Ϯ 36 mmHg) and sham (215 Ϯ 16 mmHg; P Ͻ 0.001 for both) compared with I/R (110 Ϯ 10 mmHg) and CAT (114 Ϯ 30 mmHg). Wet-dry weight ratio of I/R (6.78 Ϯ 0.94%) and CAT (6.54 Ϯ 0.87%) was significantly higher than of sham (4.85 Ϯ 0.29%; P Ͻ 0.05), which did not differ from 9B9-CAT (5.58 Ϯ 0.80%). The significantly lower degree of lung injury in 9B9-CAT-treated animals compared with I/R rats was also shown by decreased serum levels of endothelin-1 (sham, 18 Ϯ 9 fmol/mg; I/R, 42 Ϯ 12 fmol/mg; CAT, 36 Ϯ 11 fmol/mg; 9B9-CAT, 26 Ϯ 9 fmol/mg; P Ͻ 0.01) and mRNA for inducible nitric oxide synthase (iNOS) [iNOS-GAPDH ratio: sham, 0.15 Ϯ 0.06 arbitrary units (a.u.); I/R, 0.33 Ϯ 0.08 a.u.; CAT, 0.26 Ϯ 0.05 a.u.; 9B9-CAT, 0.14 Ϯ 0.04 a.u.; P Ͻ 0.001]. These results validate immunotargeting by anti-ACE conjugates as a prospective and specific strategy to augment antioxidative defenses of the pulmonary endothelium in vivo. pulmonary endothelium; monoclonal antibodies LUNG TRANSPLANTATION HAS BECOME the therapy of choice for most end-stage lung diseases. Although the number of annually performed lung transplantations is increasing it cannot keep up with the quickly rising number of recipients on the waiting list.Despite improvements in lung preservation, surgical technique, and perioperative care, early morbidity after lung transplantation because of ischemia-reperfusion (I/R)-induced lung injury remains high (9). Severe I/R injury has been described to be associated with enhanced risk for acute rejection and may lead to graft dysfunction in the long term (17,20,36).Reactive oxygen species (ROS) augment I/R i...

Anorectal malformations (ARMs) comprise a broad spectrum of conditions ranging from mild anal anomalies to complex cloacal malformations. In 40-50% of cases, ARM occurs within the context of defined genetic syndromes or complex multiple congenital anomalies, such as VATER/VACTERL (vertebral defects [V], ARMs [A], cardiac defects [C], tracheoesophageal fistula with or without esophageal atresia [TE], renal malformations [R], and limb defects [L]) association. Here, we report the identification of deletions at chromosome 13q using single nucleotide polymorphism-based array analysis in two patients with mild ARM as part of VATER/VACTERL and VATER/VACTERL-like associations. Both deletions overlap the previously defined critical region for ARM. Heterozygous Efnb2 murine knockout models presenting with mild ARM suggest EFNB2 as an excellent candidate gene in this region. Our patients showed a mild ARM phenotype, closely resembling that of the mouse. We performed a comprehensive mutation analysis of the EFNB2 gene in 331 patients with isolated ARM, or ARM as part of VATER/VACTERL or VATER/VACTERL-like associations. However, we did not identify any disease-causing mutations. Given the convincing argument for EFNB2 as a candidate gene for ARM, analyses of larger samples and screening of functionally relevant non-coding regions of EFNB2 are warranted. In conclusion, our report underlines the association of chromosome 13q deletions with ARM, suggesting that routine molecular diagnostic workup should include the search for these deletions. Despite the negative results of our mutation screening, we still consider EFNB2 an excellent candidate gene for contributing to the development of ARM in humans.

The treatment of SBS patients remains very complex. It is eminent to find the best therapeutic option for each patient and to individualize and modify the different possible types of applied techniques frequently.