University of Alabama at Birmingham

About: University of Alabama at Birmingham is a education organization based out in Birmingham, Alabama, United States. It is known for research contribution in the topics: Population & Poison control. The organization has 38523 authors who have published 86775 publications receiving 3930642 citations. The organization is also known as: UAB & The University of Alabama at Birmingham.

NADPH oxidase-4 mediates myofibroblast activation and fibrogenic responses to lung injury.

Abstract: Members of the NADPH oxidase (NOX) family of enzymes, which catalyze the reduction of O(2) to reactive oxygen species, have increased in number during eukaryotic evolution. Seven isoforms of the NOX gene family have been identified in mammals; however, specific roles of NOX enzymes in mammalian physiology and pathophysiology have not been fully elucidated. The best established physiological role of NOX enzymes is in host defense against pathogen invasion in diverse species, including plants. The prototypical member of this family, NOX-2 (gp91(phox)), is expressed in phagocytic cells and mediates microbicidal activities. Here we report a role for the NOX4 isoform in tissue repair functions of myofibroblasts and fibrogenesis. Transforming growth factor-beta1 (TGF-beta1) induces NOX-4 expression in lung mesenchymal cells via SMAD-3, a receptor-regulated protein that modulates gene transcription. NOX-4-dependent generation of hydrogen peroxide (H(2)O(2)) is required for TGF-beta1-induced myofibroblast differentiation, extracellular matrix (ECM) production and contractility. NOX-4 is upregulated in lungs of mice subjected to noninfectious injury and in cases of human idiopathic pulmonary fibrosis (IPF). Genetic or pharmacologic targeting of NOX-4 abrogates fibrogenesis in two murine models of lung injury. These studies support a function for NOX4 in tissue fibrogenesis and provide proof of concept for therapeutic targeting of NOX-4 in recalcitrant fibrotic disorders.

A novel polymorphism of FcgammaRIIIa (CD16) alters receptor function and predisposes to autoimmune disease.

Abstract: A novel polymorphism in the extracellular domain 2 (EC2) of FcgammaRIIIA affects ligand binding by natural killer (NK) cells and monocytes from genotyped homozygous normal donors independently of receptor expression. The nonconservative T to G substitution at nucleotide 559 predicts a change of phenylalanine (F) to valine (V) at amino acid position 176. Compared with F/F homozygotes, FcgammaRIIIa expressed on NK cells and monocytes in V/V homozygotes bound more IgG1 and IgG3 despite identical levels of receptor expression. In response to a standard aggregated human IgG stimulus, FcgammaRIIIa engagement on NK cells from V/V (high-binding) homozygotes led to a larger rise in [Ca2+]i, a greater level of NK cell activation, and a more rapid induction of activation-induced cell death (by apoptosis). Investigation of an independently phenotyped normal cohort revealed that all donors with a low binding phenotype are F/F homozygotes, while all phenotypic high binding donors have at least one V allele. Initial analysis of 200 patients with SLE indicates a strong association of the low binding phenotype with disease, especially in patients with nephritis who have an underrepresentation of the homozygous high binding phenotype. Thus, the FcgammaRIIIa polymorphism at residue 176 appears to impact directly on human biology, an effect which may extend beyond autoimmune disease characterized by immune complexes to host defense mechanisms.

Evaluation of the medial soft-tissue restraints of the extensor mechanism of the knee.

Abstract: We performed an anatomical dissection of the medial soft-tissue retinacular fibers that restrain lateral patellar displacement and found that the medial patellofemoral ligament inserts not only on the patella but also on the undersurface of the distal aspect of the quadriceps mechanism. The deep capsular layer contained substantial retinacular fibers that were associated with the medial patellomeniscal ligament. Functional studies of the relative contributions of the medial soft-tissue restraints in the prevention of lateral patellar displacement were also performed. Twenty-five fresh-frozen specimens of the knee, obtained after amputations (nineteen specimens) or from cadavera (six specimens) were tested biomechanically on a universal testing instrument. We ranked the soft-tissue restraints, in order of their relative contributions to the restraining force, on the basis of the percentage of force provided by the retinacular and ligamentous tissue that resisted the lateral displacement of the patella. The medial patellofemoral ligament, although varying in size and importance, was found to be the major medial soft-tissue restraint that prevented lateral displacement of the distal knee-extensor mechanism, contributing an average of 53 per cent of the total force. The patellomeniscal ligament and associated retinacular fibers in the deep capsular layer of the knee, which were previously thought to be functionally unimportant in the stabilization of the patella, contributed an average of 22 per cent of the total force. The previously described retinacular fibers (the patellotibial band) were functionally unimportant in the prevention of lateral displacement.