To assess the mechanism and specificity of polymorphonuclear leukocyte (PMN) dysfunction induced by endotoxin, rabbits were injected intravenously with 100 ,ug of Escherichia coli endotoxip, and PMN function was studied 18 to 24 h later. Compared to PMN from normal rabbits, peripheral blood PMN from rabbits injected with endotoxin showed diminished chemotactic responsiveness to two endogenous peptides, C5a (complement) and platelet-derived growth factor, and to two endogenous lipids, leukotrieRe B4 and plateletactivating factor. The chemotactic response to the synthetic chemotactic peptide, N-formyl-methionyl-leucylphenylalanine (FMLP), was unimpaired. In contrast to migration, endotoxin injection resulted in inhibition of the secretory response to the two endogenous peptides but not to the lipids or to FMLP. At a 1:4 (vol/vol) dilution, the plasma either 1 or 24 h after the endotoxin injection inhibited normal PMN chemotactic responses to C5a but not to FMLP. Similarly, at a 1:10 dilution, this plasma inhibited normal PMN chemotactic responses to leukotriene B4. The factor responsible for inhibiting responses to leukotriene B4 was anionic, specific for leukotriene B4 responses, and greater than 12,000 daltons. These data may be relevant to understanding PMN dysfunction during gram-negative sepsis.
Anterior uveitis or iritis occurs in a variety of systemic diseases including sarcoid, Behcet's, and spondyloarthritis. Iritis is, therefore, presumed to result from a variety of pathogenetic mechanisms. We hypothesized that unique chemotactic factors should be associated with different etiologies for inflammation. We have tested this hypothesis using rabbit models of anterior uveitis. We have found that aqueous humor generally contained chemotactic activity for monocytes 24 h after an intravitreal injection of endotoxin, killed mycobacteria, or human serum albumin (in a rabbit previously immunized against human serum albumin). Anterior chamber paracentesis resulted in aqueous humor with a high protein content. However, in contrast to the other models of inflammation, paracentesis did not result in a cellular infiltrate in the anterior chamber, and aqueous humor after paracentesis was not chemotactic. For either immunologically mediated inflammation or for inflammation resulting from injection of a killed bacterial product, chemotactic activity could be digested by papain or trypsin and tended to coelute with albumin on either gel filtration or ion-exchange chromatography. These observations suggest that a similar chemotactic factor for monocytes appears to be associated with ocular inflammation that follows either an immune response or injection of a killed bacterial product.
Comparative pharmacotoxicity studies in rats were per formed to evaluate the response to r-metHuIL-2[ala-125] following 2 or 4 weeks of daily intravenous or sub cutaneous administration, as well as to evaluate pharmacokinetic and pharmacodynamic responses. Pharmacokinetic analysis indicated that r-metHuIL-2[ala- 125] showed high bioavailability and nonlinear concentra tion profiles. Pharmacodynamic responses to intravenous or subcutaneous dosing with r-metHuIL-2[ala-125], as measured by white blood cell counts, were comparable. Preclinical safety studies (6, 30, and 150 μg kg-1 day -1) indi cated that r-metHuIL-2[ala-125], whether given intra venously or subcutaneously, was associated with increased circulating and infiltrating levels of lympho cytes and eosinophils. Bone marrow lymphoid hyperpla sia and splenic extramedullary hematopoiesis were simi larly observed in each study. This pattern of effects was considered an exaggerated pharmacodynamic response to r-metHuIL-2[ala-125]. Of further note was a histopatholog ic finding described as hepatocyte single cell necrosis which was observed following both intravenous and sub cutaneous administration and was considered to be a toxic response to high doses of r-metHuIL-2[ala-125]. The no observable adverse effect level (NOAEL) for r-metHuIL- 2[ala-125] via intravenous administration was 6 μg kg -1 day-1, while that for subcutaneous administration was 30 μg kg-1 day-1. Data herein present a form of rHuIL-2 with pharmacokinetic and pharmacodynamic profiles that are similar when given by these two systemic routes. Pharmacotoxic data, based on NOAELs, suggest that sub cutaneous administration may be a preferred clinical route of administration.
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