Gastrointestinal involvement in a case of hereditary angioedema: could the early weaning have had a role?

Hereditary angioedema (HAE) is a noninflammatory disorder due to reduced C1-inhibitor level and/or function and characterized by recurrent, circumscribed, and self-limiting episodes of cutaneous and mucous membrane swellings involving different organs. A heterogeneous group of mutations in the C1-inhibitor gene have been found. HAE might present with diverse clinical pictures, even within families with the same mutation, but the cause of this variability is not known yet. We describe the case of type II HAE in a young adult presenting with recurrent abdominal pain for many years, occasionally associated with ascites. We suppose that an early weaning might have influenced his phenotype, making his gastrointestinal tract a "vulnerable organ," in which hereditary angioedema could express itself.     

Vascular endothelial growth factor-A induces plaque expansion in ApoE knock-out mice by promoting de novo leukocyte recruitment

Vascular endothelial growth factor-A is widely used in clinical trials for the treatment of cardiac ischemia. VEGF-A was recently suggested to act in a proinflammatory manner, which could aggravate adjacent atherogenesis in VEGF-A-based therapy. To assess potential bystander effects, VEGF-A was focally overexpressed in advanced atherosclerotic plaques in ApoE-/- mice. Sheer-induced carotid artery plaques were transluminally incubated with Ad.hVEGF-A leading to neointimal overexpression of VEGF-A. Ad.hVEGF-A treatment of pre-existing lesions was seen to promote plaque expansion, with a concomitant increase in macrophage and lipid content, whereas it lowered collagen content. In general, Ad.hVEGF-A-treated plaques displayed a more vulnerable phenotype. VEGF-A overexpression was not accompanied by increased microvessel development in the neointima, suggesting that VEGF-A destabilizes atherosclerotic plaques through an angiogenesis-independent mechanism. Intravital microscopy confirmed that treatment with Ad.hVEGF-A led to an increased monocyte adhesion, which was mediated by a VCAM-1/PECAM-1-dependent pathway. VEGF-A indeed induced a differential expression of VCAM-1 and PECAM-1 in endothelial cells. Our data underline the importance of regular monitoring of stenotic vessels adjacent to the site of VEGF-A application. We propose that VCAM-1/PECAM-1-directed cotherapy may be an efficient strategy to prevent bystander effects of focal VEGF-A therapy in patients suffering from cardiovascular disease.     

PF-4/CXCL4 and CXCL4L1 exhibit distinct subcellular localization and a differentially regulated mechanism of secretion

PF-4/CXCL4 is a member of the CXC chemokine family, which is mainly produced by platelets and known for its pleiotropic biological functions. Recently, the proteic product of a nonallelic variant gene of CXCL4 was isolated from human platelets and named as CXCL4L1. CXCL4L1 shows only 4.3% amino acid divergence in the mature protein, but exhibits a 38% amino acid divergence in the signal peptide region. We hypothesized that this may imply a difference in the cell type in which CXCL4L1 is expressed or a difference in its mode of secretion. In different types of transfected cells, CXCL4 and CXCL4L1 exhibited a distinct subcellular localization and a differential regulation of secretion, CXCL4 being stored in secretory granules and released in response to protein kinase C activation, whereas CXCL4L1 was continuously synthesized and secreted through a constitutive pathway. A protein kinase C-regulated CXCL4 secretion was observed also in lymphocytes, a cell type expressing mainly CXCL4 mRNA, whereas smooth muscle cells, which preferentially expressed CXCL4L1, exhibited a constitutive pathway of secretion. These results demonstrate that CXCL4 and CXCL4L1 exhibit a distinct subcellular localization and are secreted in a differentially regulated manner, suggesting distinct roles in inflammatory or homeostatic processes.     

Human Fanconi A cells are susceptible to TRAIL-induced apoptosis

Tumour necrosis factor (TNF) contributes to the pathogenesis of bone marrow failure in Fanconi anaemia (FA) patients. The sensitivity of haematopoietic cells from FA, complementation group A (FANCA) subjects, who represent the majority of FA patients, to TNF-related apoptosis-inducing ligand (TRAIL) is unknown. The human lymphoblastoid FANCA HSC072 cell line and the genetically corrected counterpart HSC072FANCA-neo were tested for apoptoptic response to TRAIL using flow cytometry and Western blotting. FANCA cells were more sensitive to TRAIL-induced apoptosis than their corrected counterparts, indicating that TRAIL negatively regulates haematopoietic FANCA cell lines. This effect involved poly(ADP-ribose) polymerase-1 cleavage and caspase-8 activation.