Inhibition of αvβ5 Integrin Attenuates Vascular Permeability and Protects against Renal Ischemia-Reperfusion Injury

Ischemia-reperfusion injury (IRI) is a leading cause of AKI. This common clinical complication lacks effective therapies and can lead to the development of CKD. The αvβ5 integrin may have an important role in acute injury, including septic shock and acute lung injury. To examine its function in AKI, we utilized a specific function-blocking antibody to inhibit αvβ5 in a rat model of renal IRI. Pretreatment with this anti-αvβ5 antibody significantly reduced serum creatinine levels, diminished renal damage detected by histopathologic evaluation, and decreased levels of injury biomarkers. Notably, therapeutic treatment with the αvβ5 antibody 8 hours after IRI also provided protection from injury. Global gene expression profiling of post-ischemic kidneys showed that αvβ5 inhibition affected established injury markers and induced pathway alterations previously shown to be protective. Intravital imaging of post-ischemic kidneys revealed reduced vascular leak with αvβ5 antibody treatment. Immunostaining for αvβ5 in the kidney detected evident expression in perivascular cells, with negligible expression in the endothelium. Studies in a three-dimensional microfluidics system identified a pericyte-dependent role for αvβ5 in modulating vascular leak. Additional studies showed αvβ5 functions in the adhesion and migration of kidney pericytes in vitro Initial studies monitoring renal blood flow after IRI did not find significant effects with αvβ5 inhibition; however, future studies should explore the contribution of vasomotor effects. These studies identify a role for αvβ5 in modulating injury-induced renal vascular leak, possibly through effects on pericyte adhesion and migration, and reveal αvβ5 inhibition as a promising therapeutic strategy for AKI

Myocardial depressant effects of interleukin 6 in meningococcal sepsis are regulated by p38 mitogen-activated protein kinase

Our findings demonstrate an integral role of the p38 mitogen-activated protein kinase pathway in interleukin 6-mediated cardiac contractile dysfunction and inotrope insensitivity. Dysregulation of the p38 mitogen-activated protein kinase pathway in meningococcal septicemia suggests that this pathway may be an important target for novel therapies to reverse myocardial dysfunction in patients with meningococcal septic shock who are not responsive to inotropic support

Genes related to emphysema are enriched for ubiquitination pathways

BACKGROUND: Increased small airway resistance and decreased lung elasticity contribute to the airflow limitation in chronic obstructive pulmonary disease (COPD). The lesion that corresponds to loss of lung elasticity is emphysema; the small airway obstruction is due to inflammatory narrowing and obliteration. Despite their convergence in altered physiology, different mechanisms contribute to these processes. The relationships between gene expression and these specific phenotypes may be more revealing than comparison with lung function. METHODS: We measured the ratio of alveolar surface area to lung volume (SA/V) in lung tissue from 43 smokers. Two samples from 21 subjects, in which SA/V differed by >49 cm(2)/mL were profiled to select genes whose expression correlated with SA/V. Significant genes were tested for replication in the 22 remaining subjects. RESULTS: The level of expression of 181 transcripts was related to SA/V ( p < 0.05). When these genes were tested in the 22 remaining subjects as a replication, thirty of the 181 genes remained significantly associated with SA/V (P < 0.05) and the direction of association was the same in 164/181. Pathway and network analysis revealed enrichment of genes involved in protein ubiquitination, and western blotting showed altered expression of genes involved in protein ubiquitination in obstructed individuals. CONCLUSION: This study implicates modified protein ubiquitination and degradation as a potentially important pathway in the pathogenesis of emphysema. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/1471-2466-14-187) contains supplementary material, which is available to authorized users

Dissecting the developmental and molecular defect in split hand/ split foot malformation

grantor: University of TorontoSplit hand/split foot malformation is a human developmental limb defect that affects the central rays of the hands and feet, resulting in missing digits and claw-like extremities. Commonly segregating as an autosomal dominant disorder, this genetically heterogeneous disease displays a number of distinctive genetic features including reduced penetrance, variable expressivity, and segregation distortion, where affected males transmit the disease to their male offspring in excess of 50 percent. A SHFM locus (SHFM1) has been mapped to human chromosome 7 on the basis of a large number of patients with visible cytogenetic rearrangements. A physical map spanning this region has been generated and a 1Mb SHFM1 critical interval has been defined at 7q21.3-q22.1. This thesis describes the identification and characterization of five genes from the SHFM1 critical interval. 'DSS1', the first gene identified, encodes a putative novel acidic protein and has a developmental expression profile consistent with a role in the disease process. ' DNCI1', a cytoplasmic dynein gene, is likely not involved in the basic defect but it may be implicated in the non-Mendelian segregation observed in this disease. Two homeobox transcription factors, 'DLX5' and 'DLX6', are expressed during limb development and the known function of the related gene in 'Drosophila' further implicates them in limb development. Lastly, 'DSS2', a putative mitochondrial ATP transporter, is expressed in a specific pattern during limb development highly suggestive of role in the disease process. What is more important, ' DSS2' is the only gene identified that is directly interrupted by disease associated balanced translocation breakpoints, making it an interesting candidate. In addition, a phenotypic analysis of a mouse model for SHFM, called ' Dactylaplasia', was undertaken to further understand the disease process. It was determined that the phenotype results from the failure to maintain the central portion of the apical ectodermal ridge, a key signaling centre in the developing limb bud. It is further shown that this tissue is lost due to a lack of cellular proliferation. The data presented in this thesis provide a framework from which to begin to understand the developmental and molecular defect in SHFM.Ph.D