Four basic neutrophil chemotactic factors (chemokines) have been purified from conditioned medium of granulation tissue obtained from carrageenin-induced inflammation in the rat. On the basis of their N-terminal amino acid sequences, one of the chemokines was identical with rat GRO/cytokine-induced neutrophil chemoattractant (CINC) which we reported previously, and another was identical with rat macrophage inflammatory protein-2 (MIP-2). Two other chemokines were novel chemoattractants related to MIP-2. The novel chemokines are referred to as rat GRO/CINC-2 alpha and CINC-2 beta, and consequently CINC and rat MIP-2 are renamed rat GRO/CINC-1 and CINC-3 respectively. The complete amino acid sequences of purified CINC-2 alpha and CINC-3 were determined by analysis of the fragments isolated from proteinase V8-treated CINCs. The cDNA for CINC-2 beta was cloned by reverse transcription/PCR amplification using specific primers starting with total RNA extracted from lipopolysaccharide-stimulated rat macrophages. A comparison of the amino acid sequence encoded by the cDNA with the N-terminal amino acid sequence of purified CINC-2 beta revealed that mature CINC-2 beta is a 68-residue chemoattractant produced by cleavage of a 32-residue signal peptide. The difference in amino acid sequences between CINC-2 alpha and CINC-2 beta consisted of only three C-terminal residues. Rat GRO/CINC-2 alpha is a major chemokine, and the four purified chemokines have similar chemotactic activity, suggesting that they contribute to neutrophil infiltration into inflammatory sites in rats.
Recently we found four cytokine-induced neutrophil chemoattractants, CINC-1, CINC-2 alpha, CINC-2 beta and CINC-3/macrophage inflammatory protein 2 (MIP-2), in conditioned medium of granulation tissue obtained from carrageenin-induced inflammation in rats [Nakagawa, H., Komorita, N., Shibata, F., Ikesue, A., Konishi, K., Fujioka, M. & Kato, H. (1994) Biochem. J. 301, 545-550]. In the present report, we describe recombinant production of CINC-2 alpha, CINC-2 beta and CINC-3 in Escherichia coli, and biological properties of these chemokines. Neutrophil chemotactic activities of CINC-2 alpha and 2 beta in vitro were the same as the activity of CINC-1. CINC-3 had an activity comparable to other CINCs, but showed a decrease at high concentrations. Stimulation of neutrophils with CINCs induced an increase in intracellular [Ca2+] dose-dependently. CINC-3 was more potent than the other CINCs and still induced an increase in intracellular [Ca2+] in rat neutrophils stimulated first with other CINCs. CINC-2 alpha, CINC-2 beta and CINC-3 induced a comparable response to CINC-1 in the release of cathepsin G from rat neutrophils. Injection of CINC-2 alpha, 2 beta and 3 into preformed air-pouch on the back of rat induced infiltration of neutrophils to an extent similar to that caused by the injection of CINC-1. These data indicate CINC-2 alpha, 2 beta and 3 as well as CINC-1 are chemoattractants specific for neutrophil in vivo.
Vascular endothelial growth factor (VEGF) and its receptors have recently reported to be
expressed in human osteoarthritis (OA), suggesting that VEGF could be implicated in the
pathogenesis of this disease. In the present study, expression of VEGF in the articular
cartilage was determined in three different OA models: medial meniscectomy and
monoiodoacetate (MIA) injection in rats and age-associated spontaneous joint cartilage
destruction in guinea pigs. VEGF was detected by immunohistochemical analysis in the
regenerative and hypertrophic chondrocytes, perichondrium and osteophyte areas and
chondrocyte clones. Stain intensity of VEGF immunoreactivity increased simultaneously with
the degree of cartilage destruction and reparation. These results suggest that VEGF is a
key factor in the articular cartilage in human OA and animal OA models.
Recently we found four cytokine‐induced neutrophil chemoattractants, CINC‐1, CINC‐2α, CINC‐2β and CINC‐3/macrophage inflammatory protein 2 (MIP‐2), in conditioned medium of granulation tissue obtained from carrageenin‐induced inflammation in rats [Nakagawa, H., Komorita, N., Shibata, E, Ikesue, A., Konishi, K., Fujioka, M. & Kato, H. (1994) Biochem. J. 301, 545–550]. In the present report, we describe recombinant production of CINC‐2α, CINC‐2β and CINC‐3 in Escherichia coli, and biological properties of these chemokines. Neutrophil chemotactic activities of CINC‐2α and 2βin vitro were the same as the activity of CINC‐1. CINC‐3 had an activity comparable to other CINCs, but showed a decrease at high concentrations. Stimulation of neutrophils with CINCs induced an increase in intracellular [Ca2+] dose‐dependently. CINC‐3 was more potent than the other CINCs and still induced an increase in intracellular [Ca2+] in rat neutrophils stimulated first with other CINCs. CINC‐2α, CINC‐2β and CINC‐3 induced a comparable response to CINC‐1 in the release of cathepsin G from rat neutrophils. Injection of CINC‐2α, 2β and 3 into preformed air‐pouch on the back of rat induced infiltration of neutrophils to an extent similar to that caused by the injection of CINC‐1. These data indicate CINC‐2α, 2β and 3 as well as CINC‐1 are chemoattractants specific for neutrophil in vivo.
ABSTRACT-A novel therapeutic mechanism may be the key to improving the chief symptoms and signs of atopic dermatitis (AD), which are persistent pruritus and high serum IgE. We demonstrate here that mast cell chymase may be a possible initiating factor and that the orally active specific inhibitor Y-40613 may have a therapeutic potential in the treatment of AD. We found that Y-40613dose-dependently suppressed the scratching response in a mouse pruritus model, with inhibitory efficacy enhanced by combination with conventional drugs, suggesting that chymase contributes to the development of pruritus by a unique mechanism or mechanisms. In fact, chymase injected in the model induced the scratching response. In vitro IgE production from mouse B cells was increased by purified rat chymase and suppressed by Y-40613. Increased serum IgE observed in Brown Norway rats injected with mercury chloride was suppressed by Y-40613. Furthermore, Y-40613 lowered ear thickness as well as serum IgE level in a mouse contact dermatitis model. Taken together, these findings suggest that the specific chymase inhibitor Y-40613 may ameliorate symptoms of AD through the dual inhibition of the chymase-dependent IgE production pathway and itching sensation.
These results suggest that the optimal dose for preoperative glucose infusion, in order to preserve carbohydrate or fat metabolism, is 0.1-0.2 or 0.3 g.kg(-1).h(-1), respectively, and indicate that administration should not be discontinued until the start of surgery.
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