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Mediators in the inflammatory process


Inflammatory pain is characterized by the presence of hyperalgesia in which no painful stimuli induces activation of the sensitized primary sensory neuron (PSN). This activation is referred as overt pain. Sensitization of PSN involves the stimulation of the neuronal camp/ca2+ pathway. The most common endogenous mediator responsible for causing inflammatory hyperalgesia are the eicosanoides, in particular, PGE2. Our laboratory has been actively involved in the generalization of this concept as well in the demonstration of the ability of nonesteroidal antiinflammatory drugs to prevent the release of prostaglandins. more recently our laboratory pioneered the de demonstration that a cascade de cytokines in involved in the release of prostaglandin by any traumatic stimuli. TNF alfa plays a key role in the cascade since it initiates their release. IL-1 is the cytokine ultimately responsible for the release of PGE2 and our lab developed an analgesic based in its inhibition (at present in development). We continue to investigate other hyperalgesic cytokines (GRO, RANTES and NGF) in different models of inflammatory pain. Conversely, we are investigating the mechanism by which inhibitory cytokines ( il-4, il-10, il-13 and il-1ra) inhibit the inflammatory hyperalgesia. Parallel to those studies we have investigate the contribution of the mediators released in the spinal cord for the development of inflammatory hyperalgesia, showing that a major role of spinal glutamate that retrogradely sensitises the PSN. In the line of controlling the sensitization of the PNS, we found that the stimulation of the ARGININE/NO/CGMP pathway is involved in the analgesia produced by dipirone, diclophenac and peripheral opiates. On the other hand, we have investigate the mechanism involved on the migration and activation of the leukocytes during the inflammatory process. We described a factor released by LPS-stimulated macrophages which induces neutrophil migration when injected in the tissue and blocks the neutrophil migration when injected intravenously. This factor was named MNCF (macrophage derived neutrophil chemotactic factor). MNCF has a mw of 54 KD, PI<4.0 and has lectin-like properties with affinity to d-galactose. We aim to determine: a) aminoacid sequence of MNCF; b) to clone and express MNCF on a vector. We have also interest to understand the role of the resident macrophages, mast cells and lymphocytes on the control of the neutrophils and eosinophils emigration induced by different inflammatory stimuli. Finally, we have been investigating the contribution of the nitric oxide to different leucocytes killing against several microorganisms. (AU)