病毒性心肌炎脾脏淋巴细胞的活化与凋亡

目的:探索病毒性心肌炎(VMC)发病的脾脏机制。方法: 运用DNA缺口末端标记法、免疫组化技术检测实验组(VMC猝死者, 8例)及对照组(非心性死亡者, 4例)脾组织中细胞凋亡及主要组织相容性复合物(MHC)Ⅱ类抗原的表达情况。结果:实验组脾组织内可见大量的凋亡细胞, 脾组织MHCⅡ类抗原高表达, 动脉周围淋巴鞘MHCⅡ类抗原阳性细胞显著多于对照组;对照组脾组织内罕见凋亡细胞, MHCⅡ类抗原阳性细胞较少, 主要位于动脉周围淋巴鞘外围。结论:VMC患者脾脏免疫细胞的活化与凋亡相伴存在, 其相互作用的失衡很可能与VMC的发病机制密切相关。     

Clinical and experimental aspects of viral myocarditis.

Picornaviruses are frequently implicated as the etiological agents of acute myocarditis. This association is based historically on serological evidence of rising antibody titers to specific pathogens and more recently on identification of viral genomic material in endocardial biopsy specimens through in situ hybridization. Only rarely is infectious virus isolated from either the patient or the heart during periods of maximum myocardial inflammation and injury. Thus, despite a probable viral etiology, much interest centers on the role of the immune system in cardiac damage and the likelihood that the infection triggers an autoimmune response to heart-specific antigens. Heart-reactive antibodies and T cells are found in most myocarditis patients, and immunosuppressive therapy has proven beneficial in many, though not all, cases. Furthermore, murine models of coxsackievirus group B type 3-induced myocarditis also demonstrate that virus infection initiates autoimmunity and that these autoimmune effectors are predominately responsible for tissue injury. How virus-host interactions overcome presumed self-tolerance to heart antigens is discussed, and evidence supporting various theories of virus-initiated autoimmunity and disease pathogenesis are delineated.     

Activation of cell-survival transcription factor NFkappaB in L1Ig6-stimulated endothelial cells

Ligation of the integrin alpha(v)beta(3) in endothelial cells has been shown to be important for their survival. Such ligation induces signalling events merging into the Raf-Ras-ERK cascade that eventually induces activation of nuclear factor kappa B (NFkappaB), leading to its phosphorylation and nuclear translocation and thus inhibiting apoptosis. Here, the recombinant sixth immunoglobulin-like domain of cell adhesion molecules L1 (L1Ig6), a ligand for integrin alpha(v)beta(3), was explored as a component of vascular implant surfaces to initiate the NFkappaB-cell survival pathway. This supposition was supported. Specifically, NFkappaB-p65 was expressed in human umbilical vein endothelial cells (HUVECs) and when stimulated on L1Ig6, the phosphorylated form was found in the nucleus in over 60% of the cells. NFkappaB was not translocated into the nucleus on a number of other extracellular matrix substrates examined or when fibroblasts were cultured on L1Ig6. NFkappaB phosphorylation and nuclear translocation could be inhibited by blocking ligation of alpha(v)beta(3) by L1Ig6 with an antibody recognizing alpha(v)beta(3), with a cyclic RGD peptide, and with soluble L1Ig6. Moreover, blocking of alpha(v)beta(3) interaction with L1Ig6 was correlated with induction of apoptosis. Thus, these experiments demonstrate that L1Ig6 may be useful as alpha(v)beta(3) ligand for the induction of endothelial survival pathways mediated by NFkappaB-p65.     

Activation of Hepatic STAT3 Maintains Pulmonary Defense during Endotoxemia

Pneumonia and infection-induced sepsis are worldwide public health concerns. Both pathologies elicit systemic inflammation and induce a robust acute-phase response (APR). Although APR activation is well regarded as a hallmark of infection, the direct contributions of liver activation to pulmonary defense during sepsis remain unclear. By targeting STAT3-dependent acute-phase changes in the liver, we evaluated the role of liver STAT3 activity in promoting host defense in the context of sepsis and pneumonia. We employed a two-hit endotoxemia/pneumonia model, whereby administration of 18 h of intraperitoneal lipopolysaccharide (LPS; 5 mg/kg of body weight) was followed by intratracheal Escherichia coli (10⁶ CFU) in wild-type mice or those lacking hepatocyte STAT3 (hepSTAT3^−/−). Pneumonia alone (without endotoxemia) was effectively controlled in the absence of liver STAT3. Following endotoxemia and pneumonia, however, hepSTAT3^−/− mice, with significantly reduced levels of circulating and airspace acute-phase proteins, exhibited significantly elevated lung and blood bacterial burdens and mortality. These data suggested that STAT3-dependent liver responses are necessary to promote host defense. While neither recruited airspace neutrophils nor lung injury was altered in endotoxemic hepSTAT3^−/− mice, alveolar macrophage reactive oxygen species generation was significantly decreased. Additionally, bronchoalveolar lavage fluid from this group of hepSTAT3^−/− mice allowed greater bacterial growth ex vivo. These results suggest that hepatic STAT3 activation promotes both cellular and humoral lung defenses. Taken together, induction of liver STAT3-dependent gene expression programs is essential to countering the deleterious consequences of sepsis on pneumonia susceptibility.     

Selective up-regulation of human granulocyte integrins and complement receptor 1 by cytokines.

The percentage of human granulocytes expressing the integrins CD11b and CD11c as well as complement receptor 1 (CD35) was increased by short-term incubation of whole blood with interleukin-2 (IL-2), interleukin-4 (IL-4) and tumour necrosis factors alpha and beta (TNF-alpha and TNF-beta). The mean fluorescence intensity of granulocyte CD18 was also increased by the above cytokines, whilst that of CD11b was only increased by TNF-alpha. Up-regulation of granulocyte CD18 expression was seen with 1 U/ml of IL-2, TNF-alpha or TNF-beta, in contrast to the effect of IL-4 which was only observed with 100 U/ml. Similarly, enhanced expression of CD35 was induced by 1 U/ml of IL-2 or TNF-alpha but not by concentrations of IL-4 or TNF-beta lower than 100 U/ml. Cytokine effects on the CD11/CD18 complex and CD35 molecules were not modified by cycloheximide, suggesting that their increased expression was not due simply to synthesis de novo. None of the granulocyte surface determinants investigated was altered upon short-term incubation of blood with either IL-1, IL-6 or interferon-gamma (IFN-gamma). The demonstration in vitro that cytokines selectively up-regulate granulocyte integrins and complement receptor 1, suggests that similar mechanisms may be operating during the control of granulocyte-mediated inflammatory processes.