Proceedings of the Association of American Physicians最新文献

Phospholipase A2 (PLA2) enzymes cleave esterified fatty acids from membrane glycerophospholipids. The 20-carbon polyunsaturated fatty acid, arachidonic acid, is used as substrate by intermediate enzymes for the generation of eicosanoids, including leukotrienes and prostanoid products. An expanding number of PLA2 enzymes has now been identified that may participate in arachidonic acid release and thus serve a rate-limiting role in eicosanoid biosynthesis. Cellular PLA2 function for various members is regulated by constitutive or elicited expression, as well as by posttranslational events such as phosphorylation. In addition, the function of some cellular PLA2 enzymes is regulated by a requirement for calcium or by localization to a particular subcellular compartment. Finally, some PLA2 enzymes are secreted from the cell where they may directly interact with plasma membrane or transmembrane receptors to function as autocrine or paracrine mediators. Evaluating the roles of a number of these functionally similar PLA2 enzymes in the biosynthesis of leukotrienes and other eicosanoids is the focus of this review.

Human herpesvirus 8 (HHV-8), also termed Kaposi's sarcoma-associated herpesvirus, was identified in Kaposi's sarcoma (KS) biopsy specimens in 1994. The epidemiological data available to date indicate a strong association of HHV-8 with KS. It appears that HHV-8 is necessary for KS development. HHV-8 DNA is invariably found in all epidemiological forms of KS and primary effusion lymphomas. In contrast, HHV-8 DNA is rarely found in various tumor and nontumor tissues from patient groups not at risk of KS. Although current serology does not allow us to assess the HHV-8 prevalence in the general population, high titers of HHV-8 antibodies are almost exclusively found in KS risk groups. In addition, HHV-8 seroconversion has been shown to precede KS development. The mechanisms and genes involved in HHV-8 pathogenesis are less clear. HHV-8 belongs to a family of transforming viruses, and several candidate oncogenes have been identified by using rodent fibroblast transformation assays. However, expression of most of these genes could not be shown in latently infected tumor cells. As the HHV-8 genome encodes several cytokines and cytokine receptor homologues, HHV-8 may also promote KS pathogenesis through paraendocrine mechanisms.

5-Lipoxygenase (5-LO) catalyzes the two-step conversion of arachidonic acid to leukotriene A4 (LTA4). The first step consists of the oxidation of arachidonic acid to the unstable intermediate 5-hydroperoxyeicosatetraenoic acid (5-HPETE), and the second step is the dehydration of 5-HPETE to form LTA4. These events are the first committed reactions leading to the synthesis of all leukotrienes and play a critical role in controlling leukotriene production. 5-LO has evolved many complex structural features and regulatory mechanisms to allow it to fulfill this highly specialized role. The biology of 5-LO is reviewed here with an emphasis on enzymatic function, protein and gene structure, essential cofactors, and the many regulatory mechanisms controlling its expression.

Elucidation of the biochemistry of leukotriene production and the pharmacology of its actions has led to the development of a number of therapeutic agents shown to be of value in the treatment of asthma. These agents either prevent the synthesis of the leukotrienes, by preventing the action of the 5-lipoxygenase-activating protein or the catalytic action of the 5-lipoxygenase, or by inhibiting the action of leukotrienes at the CysLT1 receptor. Numerous clinical trials in exercise-induced asthma, allergen-induced asthma, aspirin-induced asthma, and spontaneously occurring asthmatic episodes have indicated that these agents are safe and effective asthma treatments.

Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease. Overproduction of nitric oxide (NO) has been implicated in its pathogenesis. Several retrospective studies have indicated a correlation between serum nitrate and nitrite (NOx) and disease activity. This measure of NO production can be falsely elevated by exogenous dietary and medication sources of NOx and variably reduced by serum thiols. These variables can make NOx a less reliable tool for studying the role of NO in SLE. Peroxynitrite, a by-product of NO and superoxide, nitrates tyrosine moieties. The resulting 3-nitrotyrosine (3NT) serves as a long-term indicator of NO-mediated protein modifications that is not affected by exogenous sources of NOx or serum thiols. We hypothesized that for these reasons serum 3NT levels would correlate with lupus disease activity more significantly than serum NOx. To address this hypothesis, we prospectively evaluated lupus disease activity, serum protein 3NT levels, and NOx levels in a cohort of lupus patients at 3-month intervals. Serum 3NT correlated with disease activity among African-Americans, while NOx correlated with disease activity among Caucasians. Subjects with active lupus nephritis had higher levels of serum 3NT than those without renal disease. Immunohistochemical analysis of renal biopsies from subjects with active proliferative lupus nephritis revealed renal expression of inducible NO synthase. The results of this study suggest that overproduction of NO may play a pathogenic role in SLE and lupus nephritis. Serum 3NT may be a useful, new tool for studying the contributions of NO to the pathogenesis of SLE.

Hepatitis B virus (HBV) has been shown to be linked causally to the development of hepatocellular carcinoma (HCC) in humans. One of the HBV gene products, the "X" protein, has been specifically implicated in the malignant transformation of hepatocytes; mutations in one or more of the HBV structural proteins have also been linked to HCC. HBV DNA may act as an insertional mutagen in the myc family of genes. Mutations within the pre-core and core promoter regions of HBV-DNA have also been associated with the development of HCC. Patients chronically infected with hepatitis C virus (HCV) often develop cirrhosis; a significant proportion of these patients progress to HCC. Although numerous genotypes of HCV exist, type 1b is most often associated with the eventual development of HCC in chronically infected patients. The molecular mechanisms for the malignant transformation of hepatocytes by HCV have not been elucidated.

The Epstein-Barr virus (EBV) is classically associated with three malignancies, Burkitt's lymphoma. B-cell lymphoproliferative syndromes, and nasopharyngeal carcinoma, and, more recently, with Hodgkin's disease, T-cell lymphomas, and gastric carcinoma, as well as being the causal agent for infectious mononucleosis. The relation of the virus to the malignancies varies from primary etiologic agent to necessary or contributory cofactor. Clonal EBV episomes are found in all the malignant conditions. EBV infects both epithelial and lymphoid cells, providing a pathobiological basis for these diverse associations. Most of the malignancies occur after years of viral dormancy and are accompanied or triggered by viral reactivation, in contrast to infectious mononucleosis, which results from primary infection with EBV. The EBV-associated malignancies offer insights into the causation and early detection of cancer. The molecular virology and pathobiology of EBV infection states provide the basis for the specific diagnosis of these diseases and a framework for new therapies.

Papillomaviruses have proved to be the most complex group of human pathogenic viruses. Eighty-five genotypes have been fully characterized; approximately 120 additional isolates represent only partially characterized putative novel genotypes. Specific types, most notably human papillomavirus (HPV) types 16, 18, and a few others, have been shown to cause the majority of cervical cancers and their high-grade precursor lesions. The viral oncogenes E6 and E7 are required for the initiation and maintenance of the malignant phenotype in HPV-positive cancers. Proteins coded by these genes are multifunctional and interfere with important cell cycle regulatory proteins. Expression of viral oncogenes is tightly controlled in nondifferentiated keratinocytes by at least two signaling cascades, one operative at the functional level, the other at the transcriptional level. The latter has been partially characterized. Papillomaviruses are also suspected of playing a role in a subset of oropharyngeal cancers, in squamous cell cancers of the skin, and possibly also in esophageal cancers. Clinical trials are being conducted to test the preventive and therapeutic efficacy of HPV vaccines, directed particularly against HPV 16 and 18. If proven to be effective, their global application should have a measurable effect on the worldwide incidence of cancer.