Histology and histopathology Vol.17, nº 3 (2002)
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- PublicationOpen AccessKnocked out by Rho Rac T-cell biology(Murcia : F. Hernández, 2002) Bustelo, X.R.The Rho/Rac family is a group of Ras-related proteins with demonstrated roles in the regulation of proliferation and cytoskeletal structures in a number of cell lineages. Despite this, the actual role of these proteins in T-cells could not be addressed in vivo due to the lack of adequate animal models. Recently, the use of knockout and transgenic animals for Rac1, Rac2, and RhoA has provided a genetic proof of the importance of Rho/Rac protein in different aspects of T-cell signaling. These animals have also allowed us to get better views about the influence of these GTPases proteins on the maturation decisions of immature lymphocytes and on the signaling strategies these GTPases utilize to favor the generation of coherent and robust immune responses.
- PublicationOpen AccessAbnormal cochlea linked to deafness in transgenic mice expressing human cytokeratin K8(Murcia : F. Hernández, 2002) Bartolome, M.V.; Casanova, M.Ll.; Carricondo, F.; Del Castillo, E.; Jorcano, J.L.; Gil-Loyzaga, P.The cytokeratin intermediate filaments have a relevant role in the proliferation and differentiation processes of epithelial cells. To provide information about the role of K8 cytokeratin during the auditory receptor differentiation, two groups of adult mice were used: TGK8-4 transgenic and control animals. The TGK8-4 transgenic mice contained 12 kb of K8 human cytokeratin (HK8) locus (Casanova et al., 1995, 1999). The functional activity of the auditory receptor was analyzed by auditory thresholds. Morphological studies demonstrate that the auditory receptors of the TGK8-4 transgenic mice are highly immature. Immunocytochemical studies were made by using two monoclonal antibodies: CAM 5-2 (recognizing K8 human cytokeratin) and Troma-1 (recognizing both mouse and human K8 cytokeratin). These demonstrated significant differences between the auditory receptors of the transgenic mice and the control mice. These functional and morphological differences clearly suggest that K8 cytokeratin has a relevant role during the differentiation and tridimensional organization of the sensory and the supporting cells of the auditory receptor.
- PublicationOpen AccessA micro-anatomical model of the distribution of myocardial endomysial collagen(Murcia : F. Hernández, 2002) Macchiarelli, G.; Ohtani, O.; Nottola, S.A.; Stallone, T.; Camboni, A.; Prado, I.M.; Motta, P.M.Myocardial connective tissue probably provides passive support for regulating heart tensile strength and stiffness and ultimately for controlling heart mechanics through its endomysial part. However, endomysial collagen micro-arrangement is still a matter of debate. In order to define the fine distribution of left ventricle endomysial collagen, we applied the NaOHscanning electron microscopy (SEM) maceration method (one of the techniques of choice for studying collagen micro-arrangement) to rabbit heart. Gomori-reticulum staining was used for correlated light microscopy (LM) observations. The SEM-NaOH method allowed isolation of collagen by removing other extracellular matrix components and cells and preserved collagen structure and position. Endomysial collagen appeared arranged in laminae that delimited the lacunae that were left empty by macerated myocytes and small vessels (mostly capillaries). These laminae were formed by reticular fibers, as confirmed by LM observations of Gomorireticulum- stained samples, and were organized in irregularly meshed networks made of thin (single) and thick (composed) filaments. In longitudinal views, collagen laminae extended the entire length of lacunae. In transversal views, the cut surface of the laminae appeared to be made of collagen bundles. These observations provide an updated microanatomical view of endomysial collagen distribution, which integrates previous studies. This model is based on the evidence that collagen laminae enveloped the surface of small vessels and myocytes. Thus, a type of myocyte-myocyte or capillary-myocyte "laminar connection" anchored to the entire cell length here is emphasized, rather than a type of "strut connection" anchored to defined loci, as usually described. This structure explains better how endomysium may provide the necessary support for heart compliance and protection against overstretch.
- PublicationOpen AccessPhysiology and pathophysiology of nitric oxide in the nervous system, with special mention of the islands of Calleja and the circunventricular organs(Murcia : F. Hernández, 2002) Rodrigo, J.; Alonso, D.; Bentura, M.L.; Castro-Blanco, S.; Encinas, J.M.; Fernández, A.P.; Fernández-Vizarra, P.; Richart, A.; Santacana, M.; Serrano, J.; Martínez, A.Nitric oxide (NO) has been recognized as a key regulatory factor in many physiological processes, including central nervous system function, development, and phatophysiology. NO is produced by a class of enzymes known as NO synthases (NOS) and in normal adult animals only the neuronal isoform (nNOS) is detectable. During cortical development, nNOS was found at E14 in neuroblasts of the marginal zone and its expression raised to a zenith by P5, decreasing afterwards until reaching a steady level by P10. At that time, nNOS was found mainly in pyramidal neurons. Interestingly, the inducible isoform of the enzyme (iNOS) was also active from P3 to P7, but it disappeared almost completely by P20. The neurodegeneration observed during normal aging and following hypoxic accidents seems to be the result of cumulative free radical damage, and excessive production of NO may be at the basis of the cascade. After ischemic events we observed an elevation in the number of neurons expressing nNOS coincident with an elevation in Ca2+- dependent NOS activity for up to 120 min. After this period, nNOS activity began to decrease but it was substituted by a rapid increase in Ca2+-independent activity coincident with the histological appearance of previously undetectable iNOS-immunoreactive neurons. These increases in NO production were accompanied by specific patterns of protein nitration, a process that seems to result in loss of protein function. In particular, we observed a correlation between exposure to ischemia-reperfusion and nitration of cytochrome c. This process was coincident with the exit of the cytochrome from the mitochondria to the surrounding cytoplasm, an early event in neuronal apoptosis. Interestingly, most of the morphological and molecular changes associated with ischemic damage were prevented by treatment with inhibitors of NO production, indicating a clear path in the search for efficacious drugs in the battle against cerebrovascular accidents.
- PublicationOpen AccessThe role of the angiogenic molecule VEGF in the pathogenesis of rheumatoid arthritis(Murcia : F. Hernández, 2002) Afuwape, A.O.; Kiriakidis, S.; Paleolog, E.M.The expansion of the synovial lining of joints in rheumatoid arthritis (RA), and the subsequent invasion by the pannus of underlying cartilage and bone, necessitates an increase in the vascular supply to the synovium, to cope with the increased requirement for oxygen and nutrients. New blood vessel formation - ‘angiogenesis’ - is now recognised as a key event in the formation and maintenance of the pannus in RA. Although many pro-angiogenic factors have been demonstrated to be expressed in RA synovium, the potent pro-angiogenic cytokine vascular endothelial growth factor (VEGF) has been demonstrated to have a central involvement in the angiogenic process in RA. The additional activity of VEGF as a vascular permeability factor may also increase oedema and hence joint swelling in RA. Several studies, including those from the Kennedy Institute of Rheumatology Division, have shown that targeting angiogenesis in animal models of arthritis ameliorates disease. Inhibition of angiogenesis, as an adjunct to existing therapy of RA, or even as a stand-alone treatment, would not only prevent delivery of nutrients to the synovium, but could also lead to vessel regression and possibly reversal of disease.