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Background: Systemic inflammation may be associated with resistance to nondepolarizing neuromuscular blocking drugs, the mechanisms of which are, however, uncharacterized. The authors therefore investigated the pharmacodynamics of atracurium and its relation to the expression of nicotinic acetylcholine receptors and alpha1 -acid glycoprotein in a rat model of systemic inflammation., Methods: To induce a systemic inflammation, male CD rats received 56 mg/kg corynebacterium parvum intravenously. On days 2, 4, 6, 8, 10, 12, 14, or 16 after infection, neuromuscular transmission was measured. The individual effective dose of atracurium was determined, followed by an atracurium infusion at a rate to establish a steady state neuromuscular block of 50%. Total and unbound plasma concentrations of atracurium for 50% paralysis were measured using high-performance liquid chromatography. Acetylcholine receptors were quantitated using 125I-alpha-bungarotoxin. alpha1 -Acid glycoprotein concentrations in the serum were measured using a competitive chemiluminescence immunoassay., Results: The effective dose of atracurium was increased on days 4, 6, and 8. Total atracurium plasma concentrations at 50% neuromuscular paralysis were increased on days 4, 6, 8, and 10, with a peak at day 8 (8.0 +/- 1.3 micro g/ml) compared with control rats (4.23 +/- 0.82 micro g/ml). The alpha1 -acid glycoprotein concentrations were increased between days 2 and 10, with a peak on day 4 (6.52 +/- 1.45 mg/ml), and recovered to control values (0.61 +/- 0.33 mg/ml) on day 12. Unbound plasma concentrations of atracurium to achieve 50% depression, as well as the expression of acetylcholine receptors, did not differ between groups., Conclusion: Resistance to atracurium during corynebacterium parvum-induced systemic inflammation is due to increased drug binding to alpha1 -acid glycoprotein and is unrelated to changes in acetylcholine receptor expression.

The concentrations of C-reactive protein (CRP) and alpha1-acid glycoprotein (AAG) were evaluated in 1-, 3- and 18-month-old dogs (four of each age) that had been inoculated with turpentine oil. The CRP and AAG in 3-month-old and younger dogs subjected to surgery or inoculated with either Staphylococcus aureus or a viral vaccine were also evaluated. The average CRP concentration in the sera peaked 2 days after inoculation of turpentine oil. The peak CRP concentrations in 3- and 18-month-old dogs were significantly (p < 0.05) greater than those in 1-month-old dogs. The average AAG concentration in the sera peaked 4 days after inoculation of turpentine oil. No significant difference was found in AAG concentrations between any of the age groups. When experimentally inoculated with S. aureus or subjected to oophorohysterectomy, the CRP and AAG concentrations increased in 3-month-old dogs, but they increased little in 1-month-old dogs. The CRP and AAG in dogs inoculated with the viral vaccine did not increase. In dogs with fractures or subjected to percutaneous gastrostomy, the CRP and AAG concentrations correlated with the condition of dogs.

A number of inflammatory disease states occur with greatly increased frequency in individuals inheriting the human major histocompatibility complex class I allele HLA-B27. In a minority of cases, namely those with B27-associated reactive arthritis, there is good evidence that the disease state is triggered by infection with an enteric or genitourinary bacterial pathogen. For the majority of B27-associated disease, no definite pathogenetic role for bacteria has been established. However, in these latter cases intestinal inflammation can often be demonstrated, and it sometimes occupies a major part of the clinical picture. Rats transgenic for B27 are known to develop a disorder resembling B27-associated human disease, with prominent intestinal, joint, skin, and male genital inflammatory lesions. We report here that B27 transgenic rats raised in a germfree environment do not develop inflammatory intestinal or peripheral joint disease, whereas the skin and genital inflammatory lesions are unaffected by the germfree state. These findings support the concept that gut and joint inflammation are pathogenetically closely related, and they provide direct evidence that the commensal gut flora play an important role in the pathogenesis of B27-associated gut and joint inflammation.

We measured the serum concentration of alpha 1-acid glycoprotein (alpha 1-AGP) and we evaluated the content of its hepatic mRNA in rats after 17 alpha-ethynyloestradiol treatment or after turpentine-induced acute inflammation, or after both treatments performed simultaneously. We have also studied the affinity of serum alpha 1-AGP for concanavalin A under these conditions. Both types of stimuli induce a marked retention of the glycoprotein on free concanavalin A. The serum concentration of alpha 1-AGP is increased about 14-fold compared with that in control rats when a single pharmacological dose (50 micrograms) or multiple injections of 17 alpha-ethynyloestradiol are administered. This increase is greater in turpentine-oil-injected rats (about 21-fold) and reaches a maximum (about 32-fold) in rats injected with 17 alpha-ethynyloestradiol plus turpentine oil; this increase in alpha 1-AGP corresponds to the addition of the effects of the two inducing agents. Similar changes are also observed either in the alpha 1-AGP mRNA content as estimated by using an alpha 1-AGP-specific cDNA probe, or in the amount of translatable alpha 1-AGP mRNA. The results indicate that: after a high dose of 17 alpha-ethynyloestradiol and after acute inflammation, the increase of the alpha 1-AGP serum concentration is due to an accumulation of the alpha 1-AGP mRNA; different mechanisms and/or pathways are probably involved in regulating the synthesis of alpha 1-AGP under various stimuli; 17 alpha-ethynyloestradiol as well as acute inflammation seem to control the glycosylation process of alpha 1-AGP in an identical manner.

Inflammation results in an increase in the levels of a variety of glycoproteins in serum. The glycoproteins that respond in this way are usually referred to as acute-phase reactants. Studies on the acute-phase response of rat alpha 1-acid glycoprotein showed that there was an increase in the liver levels of this glycoprotein at 12 h after turpentine inflammation. This was followed by increased serum levels at 48-72 h after inflammation, suggesting a precursor-product relationship between liver and serum alpha 1-acid glycoprotein. Incorporation studies coupled with measurements of synthesis rates of alpha 1-acid glycoprotein showed that increased synthesis was responsible for the acute-phase response of this protein to inflammation. These studies also showed that albumin was a negative acute-phase reactant. The acute-phase response of alpha 1-acid glycoprotein was accompanied by increased liver pools of UDP-N-acetylglucosamine (UDP-GlcNAc) and UDP-N-acetylgalactosamine (UDP-GalNAc) and increased liver activities of glucosamine-6-phosphate synthase and UDP-GlcNAc 2-epimerase. Activities of galactosyl and sialyl transferases in liver were also elevated and serum sialyl transferase was increased substantially in inflammation, suggesting that it may also be an acute-phase reactant. Liver activities of beta-N-acetylhexosaminidase and beta-galactosidase declined by about 50% at 24 h after inflammation; there was evidence that serum levels of these enzymes increased at 24-72 h after inflammation, suggesting that the lysosomal glycosidases may be released from liver during inflammation.(ABSTRACT TRUNCATED AT 250 WORDS)

Rat alpha 1-acid glycoprotein is an acute phase reactant which shows a marked elevation in mRNA level following inflammatory induction. It has been proposed that both transcriptional and post-transcriptional mechanisms regulate the induction of the gene. We have studied the processing of the primary transcript of alpha 1-acid glycoprotein. The preferred pathway of intron removal was determined by Northern blot analysis and was found to be unaltered after inflammatory stimulation. The final nuclear precursor did exhibit size alterations, manifest as a quantitative shift from the final precursor at 6 h to a second progressively shorter form at 18 and 24 h. Deadenylation of nuclear RNA showed that the difference in size of the precursor is due to a change in poly(A) tail length, which occurs after the splicing out of the last intron. Nuclear run-on transcription assays measured a 2.5-fold increase in transcriptional activity, with a peak at 12 h. The highest level of cytoplasmic RNA with a long poly(A) tail, however, occurs before 12 h. Our data suggest that the reduction in poly(A) tail size is due to a rapid trimming of the tail in the nucleus and that this process is modified upon inflammatory induction.

The hepatic synthesis of four "acute phase reactants" (APR), i.e., fibrinogen, alpha 1-acid glycoprotein, alpha 2-macroglobulin, and haptoglobin has been investigated in rats suffering from turpentine-induced inflammation. To follow the change in the rates of synthesis of the four APR, their concentrations were measured by immunonephelemetry in both the plasma and the hepatic microsomal fraction at various times after injury. A synchronous increase in the concentrations of these four proteins was observed in the liver (maximum 24 hours) as well as in the plasma (maximum 40 hours) of the same animals. In parallel, the site of their synthesis was localized in liver sections by light and electron microscopy using direct immunoperoxidase labeling. Of the liver cells, only the hepatocytes were labeled. In the early period of the inflammatory reaction (10 to 16 hours), synthesizing cells were detected principally in the periportal zone, but later (24 hours), the labeled area was extended to nearly the entire hepatic lobule. When serial sections of liver were examined at that time, the same cells were found to contain simultaneously the four APR. Within the cells examined by electron microscopy, the four proteins were localized in the secretory pathway, i.e., rough and smooth endoplasmic reticulum, Golgi apparatus, and secretory vacuoles. Therefore, we conclude that: (1) the experimental inflammatory reaction induces a synchronous increase in the synthesis of four APR by the liver; (2) this increased synthesis apparently results from an increased number of synthesizing hepatocytes; (3) these cells have a preferential periportal localization; and (4) individual hepatocytes are not specialized in the synthesis of a single plasma protein.