Apoptosis is a physiologic process that serves to eliminate cells during development or in response to immunologic regulation. In acute inflammation, however, apoptosis triggered by the ...overproduction of "death factors" such as TNF-alpha or Fas ligand (FasL) may contribute to tissue injury. Both TNF-alpha and FasL are presumed to convey an apoptotic signal by activating a cascade of cysteine-aspartate proteases, which includes IL-1beta-converting enzyme or caspase-1. In the present study, we evaluated the contribution of TNF-alpha and FasL, as well as the role of caspase-1, in Con A-induced hepatitis. We report here that TNF-alpha and FasL mRNA and protein levels are both increased in the livers of Con A-challenged mice. Using a novel inhibitor of TNF-alpha, we can confirm that Con A-induced hepatitis is primarily TNF-alpha dependent. Blockade of FasL with a soluble Fas immunoadhesin does not prevent liver injury in animals treated with Con A alone. However, administration of a matrix metalloproteinase inhibitor exacerbates liver injury, in part through a FasL-dependent process, since pretreatment with the soluble Fas immunoadhesin reduces liver injury in this model. In addition, mice lacking functional caspase-1 are resistant to Con A-induced hepatitis, even after pretreatment with a matrix metalloproteinase inhibitor. We conclude that TNF-alpha plays a predominant role in Con A-induced liver injury, although concomitant activation of FasL can also lead to apoptotic injury. Furthermore, Con A-induced hepatitis is caspase-1 dependent.
The antigen receptor on human T lymphocytes consists of two variable immunoglobulin-like glycoproteins, alpha and beta, which occur in association with three invariable T3 membrane proteins. In ...humans two of these proteins, T3-gamma and T3-delta, are glycoproteins of relative molecular mass (Mr) 25,000 (25K) and 20,000 (20K), respectively, while the third, T3-epsilon, is a 20K non-glycosylated protein. On the surface of murine T cells, a non-glycosylated protein dimer composed of 17K subunits (T3-zeta) is found associated with the T-cell receptor alpha and beta chains and the three T3-like polypeptide chains. It is generally accepted that major histocompatibility complex-restricted antigen recognition is a function of the alpha-beta heterodimer. This has led to the postulation that the proteins of the T3 complex are involved in the signal transduction that immediately follows antigen recognition via the antigen receptor. Events believed to be involved in early T-cell activation, such as rapid increases in phosphatidylinositol turnover and free intracellular calcium, can be triggered by antibodies directed against either the T3 complex or the clonotypic receptor. We have previously reported our findings on the cloning of the complementary DNA and genomic structure encoding both the human and murine 20K glycoprotein, T3-delta (refs 11-13). We now present our results on the cloning of the cDNA encoding the human 20K non-glycosylated chain, T3-epsilon.
To evaluate analgesic and sedative effects of medetomidine hydrochloride in dogs and to compare effects with those of xylazine hydrochloride.
Randomized, controlled trial.
184 dogs that required ...sedation or analgesia for completion of minor diagnostic or therapeutic procedures.
Dogs were sedated with medetomidine, i.v. (750 micrograms/m2 of body surface area) or i.m. (1,000 micrograms/m2) or with xylazine, i.v. (1.1 mg/kg 10.5 mg/lb of body weight) or i.m. (2.2 mg/kg 1 mg/lb). Sedative effects were measured by scoring posture and response to noise. Durations of effects were determined by measuring time intervals between drug administration and changes in posture. Analgesic effects were measured by determining toe-pinch pressure needed to elicit a withdrawal response. Clinicians rated sedative and analgesic effects and ease with which diagnostic or therapeutic procedures could be performed.
Posture and response to noise scores were significantly higher for dogs given medetomidine, i.m., than for dogs given xylazine, i.m., and for dogs given medetomidine, i.v., than for dogs given xylazine, i.v. Time to regaining sternal recumbency and time to regaining ability to stand were longest after i.m. administration of medetomidine. Toe-pinch pressures were not significantly different among groups. Clinicians rated overall analgesic and sedative effects as excellent significantly more often after administration of medetomidine than after administration of xylazine. Prevalence of adverse effects did not differ among groups.
Medetomidine and xylazine, at doses tested, were effective and safe, but results of subjective measurements indicated that medetomidine provided better sedation and analgesia than did xylazine. Specific alpha 2-adrenergic antagonists (atipamezole, yohimbine) are available for control of adverse cardiovascular effects.
