Background— Glutaraldehyde fixation (G-F) decreases but likely does not eliminate the antigenicity of bioprosthetic heart valves. Rejection (with secondary dystrophic calcification) may be why G-F xenograft valves fail, especially in young patients, who are more immunocompetent than the elderly. Therefore, we sought to determine whether rejection of G-F xenograft occurs and to correlate this with graft calcification. Methods and Results— Ascending aortas/valves (from rats [syngeneic] or guinea pigs [xenogeneic]) were transplanted (fresh or after 48 hour of G-F) into the infrarenal aortas of young rat recipients for 20 days. A xenogeneic group was also treated with steroids until graft harvest. The valves and media/adventitia were scored blindly for inflammation (0 to 4). Percent graft infiltration by T cells/macrophages was determined (immunohistochemistry), and rat IgG ELISAs were performed. There was >3 times more valve inflammation, >10 times more valve T-cell/macrophage infiltrate, and >3 times antibody rise in the G-F xenogeneic groups compared with the fresh syngeneic or the G-F syngeneic groups ( P <0.05). There was >2 times more adventitial inflammation and T-cell/macrophage infiltrate in the xenogeneic groups ( P <0.05). Steroid treatment decreased inflammation and antibody rise in the xenogeneic groups ( P <0.05). Correlation analysis revealed media/adventitia inflammation ( P =0.02) and percent macrophage ( P =0.01) infiltration to be predictors of calcification. Conclusions— G-F xenografts have cellular/humoral rejection and calcify secondarily.
We used Affymetrix Microarrays to define interferonc (IFN-c )-dependent, rejection-induced transcripts (GRITs
Hepatitis C virus (HCV) is a blood-borne pathogen and a major cause of liver disease worldwide. Gene expression profiling was used to characterize the transcriptional response to HCV H77c infection. Evidence is presented for activation of innate antiviral signaling pathways as well as induction of lipid metabolism genes, which may contribute to oxidative stress. We also found that infection of chimeric SCID/Alb-uPA mice by HCV led to signs of hepatocyte damage and apoptosis, which in patients plays a role in activation of stellate cells, recruitment of macrophages, and the subsequent development of fibrosis. Infection of chimeric mice with HCV H77c also led an inflammatory response characterized by infiltration of monocytes and macrophages. There was increased apoptosis in HCV-infected human hepatocytes in H77c-infected mice but not in mice inoculated with a replication incompetent H77c mutant. Moreover, TUNEL reactivity was restricted to HCV-infected hepatocytes, but an increase in FAS expression was not. To gain insight into the factors contributing specific apoptosis of HCV infected cells, immunohistological and confocal microscopy using antibodies for key apoptotic mediators was done. We found that the ER chaperone BiP/GRP78 was increased in HCV-infected cells as was activated BAX, but the activator of ER stress–mediated apoptosis CHOP was not. We found that overall levels of NF-κB and BCL-xL were increased by infection; however, within an infected liver, comparison of infected cells to uninfected cells indicated both NF-κB and BCL-xL were decreased in HCV-infected cells. We conclude that HCV contributes to hepatocyte damage and apoptosis by inducing stress and pro-apoptotic BAX while preventing the induction of anti-apoptotic NF-κB and BCL-xL, thus sensitizing hepatocytes to apoptosis.
Summary 1.Plants produce a variety of secondary metabolites such as flavonoids or tannins that vary in effectiveness against different herbivores. Because invasive plants experience different herbivore interactions in their introduced versus native ranges, they may vary in defence chemical profiles. 2. We subjected tallow tree (Triadica sebifera) seedlings from native (China) and introduced (US) populations to induction by leaf clipping or one of three Chinese caterpillars (two generalists and one specialist). We measured the concentrations of five flavonoids and four tannins in leaves produced before or after damage. We measured growth of caterpillars fed these leaves from plants of each induction treatment or undamaged controls. 3. Plants from introduced populations had higher flavonoids and lower tannins than plants from native populations, especially in new leaves following induction. Caterpillar responses to changing chemical concentrations varied in direction and strength, so overall performance varied from significantly lower (generalist Grammodes geometrica), unchanged (generalist Cnidocampa flavescens), to significantly higher (specialist Gadirtha inexacta) on introduced populations. 4. Synthesis. Together, such a trade-off in secondary metabolism in invasive plants and the effect on herbivores suggest divergent selection may favour different chemical defences in the introduced range where co-evolved natural enemies, especially specialists, are absent.
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