Biomedical subjects

Mark D Wewers

Publications and source records attributed to Mark D Wewers.

23 records · Page 2Linked to original sources

PubMed2003

Respiratory symptoms among HIV-seropositive individuals.

STUDY OBJECTIVES: Recent evidence suggests that chronic or latent viral infection may be an important predisposing factor in the development of COPD among smokers. As such, understanding if HIV-seropositive smokers are at heightened risk for respiratory symptoms may have relevance with regard to COPD pathogenesis. The current study was done to systematically identify the prevalence of respiratory symptoms among an HIV-seropositive population and to identify associated clinical features. DESIGN AND SETTING: Cross-sectional analysis at an academic medical center. PARTICIPANTS: Three hundred twenty-seven HIV-seropositive individuals without a history of AIDS-related pulmonary complications. Fifty-two HIV-negative individuals with a similar age and smoking history served as a comparison group. MEASUREMENTS: Administration of the American Thoracic Society Division of Lung Diseases respiratory questionnaire, and pulmonary function studies. RESULTS: Respiratory symptoms including dyspnea (41.6% vs 7.7%), cough (40% vs 25%), and phlegm production (41.9% vs 23.1%) were extremely common in the HIV-group and significantly more common than in the HIV-negative group. Current or prior cigarette smoking was the most important predictor of respiratory symptoms among the HIV-seropositive group. The use of the antiretroviral agent lamivudine was associated with a significant reduction in dyspnea. CONCLUSION: HIV-seropositive individuals are at increased risk for the development of respiratory symptoms even prior to the onset of AIDS-related pulmonary complications. This may reflect a heightened susceptibility to the effects of cigarette smoking.

Adult↗

PubMed2002

Cyclosporin A ameliorates mitochondrial ultrastructural injury in the ileum during acute endotoxemia.

OBJECTIVE: This study was designed to determine the role, if any, of the mitochondrial permeability transition in the pathogenesis of mitochondrial injury in a representative systemic organ during the acute phase of endotoxemia. DESIGN: A well-established, normotensive feline model was employed to determine whether pretreatment with cyclosporin A, a potent inhibitor of the mitochondrial permeability transition, reduces the severity of mitochondrial injury in the ileum during acute endotoxemia. SETTING: The Ohio State University Medical Center research laboratory. SUBJECTS Adult, male conditioned cats. INTERVENTIONS: Volume resuscitation and maintenance of acid/base balance and tissue oxygen availability were provided, as needed, to minimize the potentially confounding effects of tissue hypoxia and/or acidosis on the experimental results. Following isotonic saline vehicle (control; n = 6), lipopolysaccharide (3.0 mg/kg, intravenously; n = 10), or cyclosporin A (6 mg/kg, intravenously; n = 7) followed in 60 mins by lipopolysaccharide (3.0 mg/kg, intravenously) administration, ileal samples were obtained at 4 hrs posttreatment, and mitochondrial ultrastructure was assessed. Objective comparisons of mitochondrial ultrastructural morphology were performed by using digital image analyses. MEASUREMENTS AND MAIN RESULTS: As expected, significant mitochondrial injury was apparent in the ileal tissues by 4 hrs following LPS treatment, despite maintenance of regional tissue oxygen availability. Objective evaluation of mitochondrial morphology demonstrated characteristics consistent with high-amplitude swelling. Cyclosporin A pretreatment protected against the development of these LPS-induced mitochondrial ultrastructural abnormalities, an effect not attributable to the suppression of lipopolysaccharide-induced tumor necrosis factor-alpha production. CONCLUSIONS: These investigations are the first to demonstrate a protective effect of cyclosporin A against mitochondrial injury in a representative systemic organ during acute endotoxemia. We propose that mitochondrial injury likely related to induction of the mitochondrial permeability transition may participate in the pathogenesis of systemic organ injury and organ failures during acute sepsis.

Analysis of Variance↗

PubMed2002

Opposing effect by cytokines on Fas-mediated apoptosis in A549 lung epithelial cells.

Tissue repair is determined by many signals provided in the local environment. Central to this process is the commitment of the parenchymal cell to undergo apoptosis, survive, or proliferate following inflammation. We hypothesize that lung epithelial cell apoptosis is influenced by exposure to cytokines released into the alveolar microenvironment during the inflammatory process. In this investigation we demonstrate that interferon (IFN)-gamma and interleukin (IL)-1beta have opposing effects on Fas-mediated apoptosis in A549 cells, a human lung epithelial cell line. Exposure to IFN-gamma before Fas activation significantly increased caspase activity, caspase processing of CK-18, a key cytoskeletal protein in epithelial cells, and increased the appearance of apoptotic nuclei. Induction of Fas-mediated death by IFN-gamma was 3-fold higher than with Fas activation alone. In contrast, pretreatment with IL-1beta before Fas activation completely inhibited apoptosis. Furthermore, our results demonstrate that IFN-gamma and IL-1beta induce opposite effects at multiple checkpoints during Fas-mediated apoptosis. Most striking, IL-1beta prevented the activation of caspases involved in Fas-mediated death by inducing an anti-apoptotic effect proximal to or at the point of caspase-8 activation. Finally, our investigation demonstrates that the differential impact of IL-1beta and IFN-gamma on Fas-mediated apoptosis are in part dependent on modulation of the PI 3-K/Akt survival pathway.

Apoptosis↗

PubMed2001

Regulated expression and inhibitory function of Fcgamma RIIb in human monocytic cells.

Human monocytes/macrophages express three classes of receptors for IgG: FcgammaRI, FcgammaRII, and FcgammaRIII. The expression and function of these receptors has been extensively studied with the exception of one, FcgammaRIIb. While the mRNA for FcgammaRIIb has been detected in human monocytes, the protein has remained elusive. Studies in mouse models indicated that the macrophage FcgammaRIIb serves to down-regulate FcgammaR-mediated phagocytosis and immune complex-induced inflammation. FcgammaRIIb has also been shown to modulate the action of cytotoxic antibodies against tumors in mouse models. Hence, an understanding of how FcgammaRIIb expression is regulated is of great importance. Here we demonstrate for the first time FcgammaRIIb protein expression and function in human monocytes. We also report that the expression of FcgammaRIIb is highly up-regulated by interleukin-4, a Th2 cytokine, and that the up-regulation of FcgammaRIIb results in a decrease in the phagocytic efficiency of interleukin-4-treated THP-1 cells. Furthermore co-clustering FcgammaRIIb with FcgammaRIIa resulted in enhanced phosphorylation of the inositol phosphatase SHIP, association of SHIP with Shc, and phosphorylation of additional proteins around 120 and 60-65 kDa, with a concomitant attenuation of Akt activation. We, therefore, propose that FcgammaRIIb serves to inhibit FcgammaRI/IIa-mediated macrophage activation using SHIP as its effector.

Animals↗

PubMedDate not supplied

Adiponectin inhibits superoxide generation by human neutrophils.

Adiponectin (Ad), a member of the adipocytokine family, has been reported to possess antiinflammatory properties. We investigated the effects of full-length human Ad (hAd) on phorbol 12-myristate 13-acetate (PMA)-induced O2-* generation by human neutrophils. hAd, even at the lowest tested concentration of 0.001 microg/ml, after 30-min pretreatment of cells, significantly inhibited O2-* generation by neutrophils stimulated with PMA (100 nM). However, no relation between the dose of hAd and extent of inhibition of PMA-induced O2-* generation was observed with increasing the concentration of hAd up to 1 microg/ml. hAd also significantly inhibited neutrophil O2-* generation stimulated by N-formyl-methionyl-leucyl-phenylalanine (100 microM) and diacylglycerol (500 nM), as well as the PMA-induced neutrophil nitroblue tetrazolium reduction and H2O2 formation. Pretreatment of neutrophils with pronase-digested hAd failed to inhibit the PMA-induced O2-* generation. For the first time, this study revealed that Ad inhibited O2-* generation by neutrophils, possibly through regulation of NADPH oxidase.

Adiponectin↗