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C C Nast

Publications and source records attributed to C C Nast.

At least 19 recordsLinked to original sources
PubMed1992

Recombinant interleukin-1 receptor antagonist blocks the proinflammatory activity of endogenous interleukin-1 in rabbit immune colitis.

The effects of human recombinant interleukin-1 receptor antagonist (IL-1ra) on inflammation, tissue damage, and production of inflammatory mediators in rabbit formalin-immune complex colitis were examined. Treatment of rabbits with intravenous administration of IL-1ra before and periodically throughout the first 43 hours after the induction of colitis (total 7 doses) suppressed inflammation and tissue damage in a dose-related manner. Maximum inhibition of inflammatory index (from 3.0 +/- 0.3 to 0.8 +/- 0.3, P less than 0.001), edema (from 2.3 +/- 0.2 to 0.6 +/- 0.2, P less than 0.001), percent of mucosal necrosis (from 44% +/- 7% to 7% +/- 3%, P less than 0.02) and myeloperoxidase (MPO) activity (from 4.9 +/- 1.0 U/g to 1.0 +/- 0.3 U/g, P less than 0.001) occurred with the dose of 5 mg/kg. Colonic prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) production, measured in rectal dialysates by specific radioimmunoassays, was also dose dependently suppressed (from 1124 +/- 319 pg/mL to 190 +/- 75 pg/mL, P less than 0.001 and 568 +/- 192 pg/mL to 92 +/- 51 pg/mL, P less than 0.001, respectively, at 5 mg/kg). In contrast, colonic IL-1 alpha tissue levels measured by a specific radioimmunoassay after tissue extraction were similar in all groups. When only two doses of IL-1ra, 10 minutes before and 3 hours after the induction of colitis were given, there was no longer an inhibitory effect on inflammation or production of inflammatory mediators. However, delaying the initial IL-1ra treatment 3 hours after the induction of colitis (total 6 doses) was effective in reducing inflammatory index (by 60%), MPO activity (by 79%), PGE2 (by 62%), and LTB4 (by 72%) whereas colonic IL-1 alpha levels were unchanged compared with vehicle-treated animals. These studies show the ability of human recombinant IL-1 receptor antagonist to suppress the proinflammatory activity of IL-1 produced in the colon during the induction and progression of rabbit immune complex colitis.

Animals↗
PubMed1992

Early increased renal procollagen alpha 1(IV) mRNA levels in streptozotocin induced diabetes.

Changes in renal procollagen mRNA levels were measured shortly after the induction of streptozotocin induced diabetes in the rat. "Medullary" procollagen alpha 1(IV) levels seven days after diabetes induction was significantly higher in untreated diabetic rats (DM, N = 12; 244 +/- 57% of the mean control value), than in diabetic rats receiving small doses of insulin insufficient to achieve euglycemia (NPH, N = 10; 87 +/- 12%) and in diluent injected nondiabetic control rats (C, N = 15; 100 +/- 12%; P less than 0.01, DM vs. C and DM vs. NPH). "Medullary" procollagen alpha 1(I) mRNA levels were numerically increased in DM to a lesser degree (141 +/- 5%, ANOVA not significant) compared to C (100 +/- 13%), and this small increment was further normalized by insulin treatment (NPH, 120 +/- 11%). A trend for increased beta-actin mRNA levels in DM did not reach significance (P greater than 0.05). Increases in "medullary" procollagen mRNA levels did not correlate with kidney weight, glomerular tuft volume, creatinine clearance, food intake, or body weight gain, and occurred when renal morphology was normal by light microscopy. Statistically significant but weak correlations were noted between the serum glucose levels and "medullary" procollagen alpha 1(IV) mRNA levels (r = 0.43, P less than 0.05). In addition, weak correlations were noted between glycosuria and "medullary" procollagen alpha 1(I) levels (r = 0.38, P less than 0.05). In situ hybridization studies localized the increased procollagen alpha 1(IV) mRNA levels predominantly in the DM group primarily in the deep cortex and medullary outer stripe of proximal tubules. Glomerular procollagen alpha 1(IV), alpha 1(I), alpha 1(III) and beta-actin mRNA levels were not increased in untreated diabetic rats 7 or 28 days after diabetes induction. Thus, tubular procollagen alpha 1(IV) mRNA levels increased prior to any measurable change in glomerular levels and were ameliorated by insulin administration.

Animals↗
PubMed1992

Effects of alginase on the natural history and antibiotic therapy of experimental endocarditis caused by mucoid Pseudomonas aeruginosa.

The exopolysaccharide (alginate) of mucoid strains of Pseudomonas aeruginosa is believed to be an important virulence factor. The ability of an alginate-deploymerizing enzyme (alginase) to modify the polymorphonuclear leukocyte (PMN)-directed and antibiotic-mediated phagocytosis and killing of mucoid P. aeruginosa was studied both in vitro and in vivo. In vitro, pretreatment of a mucoid P. aeruginosa strain (144MR) resulted in a significant enhancement of PMN phagocytosis and killing of the organism (P less than 0.05), to levels similar to that observed with its nonmucoid mate, strain 144NM. Moreover, alginase treatment of the mucoid strain 144MR caused a substantial removal of bacterial cell surface alginate as assessed by immunofluorescence staining with a murine monoclonal antialginate antibody. The experimental endocarditis model was used to evaluate the in vivo effect of alginase in modifying the course of a deep-seated pseudomonal infection caused by mucoid strain 144MR. In right-sided endocarditis, in which PMNs normally mediate spontaneous clearance of the organism from cardiac vegetations (A. S. Bayer, J. Yih, C. Y. Chiu, and C. C. Nast, Chemotherapy 35:278-288, 1989), the presence of the alginate exopolysaccharide on strain 144MR was associated with an inability to reduce intravegetation pseudomonal counts over a 13-day postinfection period; in contrast, right-sided vegetations infected with the nonmucoid strain 144NM underwent significant reductions in bacterial densities over this same time (P less than 0.05). Administration of alginase intravenously (i.v.) (750 enzyme units per day for 7 days) to animals with right-sided endocarditis caused by the mucoid strain 144MR was associated with a significant reduction in intravegetation pseudomonal counts (P less than 0.05), to levels similar to that seen with endocarditis caused by the nonmucoid strain. In left-sided endocarditis caused by mucoid strain 144MR, animals received either no therapy, amikacin (20 or 40 mg/kg twice a day for 7 or 14 days), or amikacin plus alginase (750 U/day [i.v.]). The coadministration of alginase for 14 days with the higher-dose amikacin regimen rendered more left-sided vegetations culture negative than those in animals receiving the antibiotic alone for 7 or 14 days (P = 0.001 and 0.056, respectively). These salutary effects of alginase in vivo were paralleled by the ability of the enzyme to remove the exopolysaccharide from the surface of mucoid pseudomonal cells within cardiac vegetations, as assessed by transmission electron microscopy.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1992

Acquired cystic disease in chronically rejected renal transplants.

Acquired cystic disease has been documented to complicate most forms of chronic renal damage; it has only infrequently been described in transplanted kidneys. Five patients with noncystic ESRD and chronically rejected transplants in which acquired cystic disease arose are reported. The diagnosis of acquired cystic disease was established in examination of transplant nephrectomies from four patients and a core biopsy from the fifth. The allografts were in place from 44 to 80 months; three patients were treated with hemodialysis before the diagnosis of acquired cystic disease, whereas two received peritoneal dialysis. Three of the four patients evaluated had cysts in the native kidneys. Although papillary hyperplasia of lining epithelium was evident in four specimens, only one kidney was the site of neoplasms in the form of multiple small tubular adenomas. No malignant neoplasms were noted in this study or in the few similar previous ones; however, it is possible that chronically rejected transplanted kidneys may harbor neoplasms with the same malignant potential as those in acquired cystic disease in native kidneys.

Adult↗
PubMed1992

Laminin B1 is preferentially expressed in the cortex of rat kidney and is not affected by cyclosporine administration.

Cyclosporine has proven beneficial as an immunosuppressive agent for organ rejection in kidney transplants as well as in heart and liver transplants. Cyclosporine administration, however, is associated with certain adverse effects, one of the most important being chronic nephrotoxicity characterized by focal cortical scarring. Recent experimental data show involvement of type I and possibly type IV collagens in this process. Because laminin represents another potential extracellular matrix target, we examined the effects of cyclosporine administration in rats on the expression of laminin at the messenger ribonucleic acid (mRNA) and protein levels. In untreated normal rats, laminin B1 mRNA is preferentially expressed in the renal cortices, as demonstrated by northern blots. Daily administration of cyclosporine leads to focal cortical interstitial fibrosis and tubular atrophy by 4 weeks with, as shown previously, elevated procollagen alpha-1 (type I) mRNA levels at 1 and 4 weeks. In contrast, the amounts of message for laminin B1 remain identical after 1 week and 4 weeks of cyclosporine administration, despite the development of fibrosis at 4 weeks. Similar results were obtained with antilaminin antibody. We conclude that laminin is abundant in renal cortical tissues as compared with its medullary contents and is not altered in the process of renal cortical fibrosis induced by cyclosporine.

Animals↗
PubMed1991

Calcitonin gene-related peptide and substance P decrease in the rabbit colon during colitis. A time study.

The sensory neuropeptides, substance P and calcitonin gene-related peptide, have been implicated in inflammatory reactions in several tissues. An immune-complex model of colitis was used in rabbits to determine the colonic content (nmol/g protein) of immunoreactive substance P and calcitonin gene-related peptide at various times after induction of inflammation to assess changes in these neuropeptides during the inflammatory response. Calcitonin gene-related peptide content was decreased by 66% 4 hours after induction of inflammation and reached a maximum of 80% at 48 hours. The substance P content was decreased at 8 hours, with a maximum decrease of 64% at 48 hours. Substance P decrease was detected in the muscle layer. The amounts of substance P in the mucosal/submucosal layer extracts were too low to allow accurate measurements. Calcitonin gene-related peptide decreased both in the muscle and the mucosal-submucosal layers. Immunohistochemical analysis showed that calcitonin gene-related peptide and substance P innervation patterns were comparable in normal and inflamed colon, even though there appeared to be a decrease in density and intensity of the staining, particularly for calcitonin gene-related peptide at 48 hours. The early decrease of calcitonin gene-related peptide and substance P during the time course of colitis might be due to release from nerve terminals of the gut during the inflammatory response. The profound changes in colonic calcitonin gene-related peptide and substance P content during colitis may have important implications during inflammation and subsequent tissue repair and may also lead to disturbances in gut motility.

Animals↗
PubMed1991

Evaluation of fine-needle aspiration biopsy in the diagnosis of renal transplant dysfunction.

Fine-needle aspiration biopsy (FNAB) was performed in 41 renal transplant patients to assess its value in the diagnosis of the cause of graft dysfunction. The procedure was used on 71 occasions, and in each case a clinical diagnosis was made and compared with the cytological diagnosis made independently by a pathologist. When available, core biopsy histopathology was used to confirm the final diagnosis. Fifty-seven (80%) of the aspirates yielded adequate material. A clinical diagnosis of acute cellular rejection (ACR) was made in 21 patients, 18 (78%) of whom showed confirmatory immune activation on FNAB. The clinical diagnosis of either acute tubular necrosis (ATN) or cyclosporine toxicity was confirmed in 31 (91%) of 34 aspirates. In eight aspirates, the cytological diagnosis was different than that made clinically. Humorally mediated vascular rejection, and lymphocytosis secondary to causes other than rejection, such as viral infection, were considered as possible causes of this discrepancy. Provided that adequate samples are obtained. FNAB is valuable in the clinical management of renal transplant patients. Its accuracy should not be overestimated and the results obtained should be evaluated in the light of the overall clinical picture.

Biopsy, Needle↗
PubMed1991

Cyclosporine induces elevated procollagen alpha 1 (I) mRNA levels in the rat renal cortex.

Chronic cyclosporine nephrotoxicity is a poorly understood drug side-effect characterized by renal cortical interstitial scarring. To evaluate procollagen mRNA levels as an early factor in the development of this form of renal fibrosis, we measured renal procollagen alpha 1 (I), alpha 1 (III), alpha 1 (IV) and beta-actin mRNA levels in rats treated with cyclosporine (CsA) or the olive oil vehicle (OO) for one or four weeks. Renal morphology was similar without atrophy or fibrosis in one week CsA and OO and four week OO rats. Four week CsA rats had focal cortical interstitial fibrosis and tubular atrophy. Cortical procollagen alpha 1 (I) mRNA levels were increased in CsA versus OO rats at one week (P less than 0.02) and four weeks (P less than 0.02). One week medullary procollagen alpha 1 (I) and all other one week medullary, and one and four week cortical procollagen and beta-actin mRNA levels were no different in CsA versus OO rats. The early increase in renal cortical procollagen alpha 1 (I) mRNA levels precedes renal morphologic abnormalities, and may represent an important step in the pathogenesis of cyclosporine-induced renal cortical fibrosis.

Actins↗
PubMed1991

Functional role of mucoid exopolysaccharide (alginate) in antibiotic-induced and polymorphonuclear leukocyte-mediated killing of Pseudomonas aeruginosa.

We evaluated in vitro the functional role of mucoid exopolysaccharide (MEP) of Pseudomonas aeruginosa in blocking antibiotic-induced and polymorphonuclear leukocyte (PMN)-mediated pseudomonal killing. The serum-resistant P. aeruginosa isolates used were mucoid strain 144MR and its nonmucoid revertant, strain 144NM. By timed kill curves, early bacterial effects of amikacin against mucoid strain 144MR were substantially less than those observed with nonmucoid strain 144NM; this effect was reversible with enzymatic hydrolysis of MEP of strain 144MR by alginase. Also, early tobramycin uptake (15 to 30 min) by mucoid 144MR cells was less than that seen with nonmucoid strain 144NM; pretreatment of 144MR cells with alginase substantially enhanced early tobramycin uptake compared with untreated 144MR cells (P = 0.08). In strain 144NM (but not in strain 114MR) there was a notable postantibiotic leukocidal enhancement effect manifested by increased nonopsonic killing following brief exposure of these cells to supra-MIC amikacin; pretreatment of strain 144MR with alginase rendered these cells more susceptible to amikacin-induced postantibiotic leukocidal enhancement. Similarly, direct PMN-mediated nonopsonic killing of mucoid strain 144MR was significantly less than that observed with strain 144NM (P less than 0.05); pretreatment of 144MR cells with alginase rendered this strain equal to strain 144NM in susceptibility to nonopsonic killing. In addition, exogenous sodium alginate or extracted MEP of strain 144MR interfered with effective nonopsonic killing of strain 144NM by PMNs. Studies also indicated that mucoid strain 144MR was phagocytosed significantly less well than its nonmucoid mate (P less than 0.00001), an effect reversed by pretreatment of the mucoid cells with alginase. These data confirm that P. aeruginosa MEPs functionally decrease the uptake and early bactericidal effect of aminoglycosides in vitro and interfere with effective PMN-mediated nonopsonic phagocytosis and killing of mucoid strains.

Alginates↗
PubMed1991

Differentiation of cytomegalovirus infection from acute rejection using renal allograft fine needle aspirates.

Cytomegalovirus (CMV) infection is an important cause of renal allograft dysfunction and may be difficult to distinguish from acute transplant rejection both clinically and histologically. To establish the early diagnosis of CMV infection, we used immunohistochemical staining with antibodies against CMV early nuclear protein (CMV-A) and histocompatibility leukocyte class II antigen (DR) in renal transplant fine needle aspirates. Fifty-eight aspirates from 27 patients were assessed, 53 for CMV-A and 53 for DR. Positive staining was defined as greater than or equal to 35% stained tubular cells for CMV-A and greater than or equal to 30% stained tubular cells for DR. Clinical diagnoses were made retrospectively without using the information obtained from aspirate diagnoses. CMV-A staining was negative in 44 aspirates, none at the time of CMV infection. CMV-A was positive in nine aspirates, seven during CMV infection (78%, P less than 0.00001 versus CMV-A negative). DR staining was never present in the absence of acute rejection. All aspirates performed during acute rejection had positive DR staining (P less than 0.00001 versus DR negative). Aspirates with acute rejection comprised 80% of all DR-positive aspirates, whereas those with CMV infection included only 13%. The percent CMV-A staining increased with CMV disease progression; DR staining decreased after successful treatment of acute rejection. These data demonstrate that CMV-A staining is associated with CMV infection whereas DR staining is not. DR staining is specifically related to acute rejection. CMV-A and DR staining of fine needle aspirates is a potentially valuable diagnostic tool to distinguish rapidly between CMV infection and acute transplant rejection as the etiology of renal allograft dysfunction.

Antigens, Viral↗
PubMed1991

Neuropeptides and inflammatory bowel disease.

Pronounced changes in gut neuropeptide content and innervation patterns have been observed in the inflamed intestine of patients with inflammatory bowel disease. It is not known to date whether these changes in neuropeptides are due to altered synthesis and release from intrinsic and/or extrinsic neurons and nerve fibers. The changes in circular smooth muscle response associated with diminished VIP in the intestine of patients with Crohn's disease suggests that VIP may play an important role in the pathophysiology of motility in IBD. The pronounced increase in SP receptors at small vessels in all gut layers and at lymph nodules in the inflamed intestine of IBD patients supports the hypothesis that SP is a modulator of inflammation in IBD and possibly acts by release from extrinsic sensory nerves of the gut. Sensory nerve may play a role not only in enhancing an inflammatory response in the intestine, but also in tissue repair. An inflammatory response after tissue injury and subsequent wound healing presumably is the normal response in healthy tissue. In IBD however, this sequence may be deeply disturbed by an unrestricted immune response which does not lead to or delays intestinal tissue healing. Although it is intriguing to postulate that interactions between the immune system and nervous system exist and play a role in the pathophysiology of intestinal inflammation, in vivo studies blocking or mimicking neuropeptide action are needed to prove this bidirectional communication.

Gastrointestinal Motility↗
PubMed1991

Frozen-section analysis of allograft renal biopsy specimens. Reliable histopathologic data for rapid decision making.

Rapid tissue diagnosis during acute events associated with renal transplantation is often necessary to permit immediate decisions regarding initiation or modification of therapy. To achieve this, we performed frozen section analyses with cryoprotected alcoholic Bouin's-fixed tissue, which permits evaluation within 2.5 hours. During a 30-month period, 200 allograft biopsies were performed; 68 frozen sections were obtained when deemed necessary by the clinical team. We compared frozen-section diagnoses with those following regular evaluation of the biopsy specimen. Agreement in diagnoses occurred in 61 (88.4%) of 69 specimens. Acute rejection was the dominant diagnosis (n = 39); others were acute tubular necrosis, cyclosporine toxicity, chronic rejection, and infection. Major misdiagnoses included acute vascular processes (three capillary and/or venous thromboses and one vascular inflammation); acute cellular rejection was missed in two cases, reflecting a sampling error. Secondary diagnoses not of immediate therapeutic importance were detected in seven frozen sections and missed in nine. These included chronic glomerulopathies, nephrosclerosis, and mild chronic rejection. Although acute vascular phenomena may be difficult to recognize in frozen sections, we conclude that allograft biopsy frozen-section analysis is a valuable part of the care of transplant recipients.

Biopsy↗
PubMed1990

Chemotactic peptide-induced acute colitis in rabbits.

Bacterial chemotactic peptides from the intestinal lumen could potentially induce inflammation if they reached the mucosa. We tested several peptides chemotactic for different inflammatory cells, as well as a nonchemotactic peptide, bradykinin, for their ability to induce colitis in vivo in rabbits. These peptides were also assessed for their ability to stimulate release of the eicosanoids leukotrienes B4 and C4 and prostaglandin E2 from normal rabbit colons perfused ex vivo. Intracolonic administration of n-formyl-methionyl-leucyl-phenylalanine (chemotactic for neutrophils); its methyl ester (chemotactic for monocytes), and alanyl-glycyl-seryl-glutamic acid (chemotactic for eosinophils) all produced colitis (assessed grossly and histologically) within 4 days. Bradykinin did not induce colitis although it did release prostaglandin E2. n-Formyl-methionyl-leucyl-phenylalanine methyl ester induced the greatest degree of colitis in vivo and released prostaglandin E2 and leukotrienes ex vivo. n-Formyl-methionyl-leucyl-phenylalanine and alanyl-glycyl-seryl-glutamic acid induced comparable degrees of inflammation, but alanyl-glycyl-seryl-glutamic acid produced no eicosanoid release while n-formyl-methionyl-leucyl-phenylalanine released both prostaglandin E2 and leukotriene B4 and leukotriene C4 products from normal ex vivo perfused colons. Thus alanyl-glycyl-seryl-glutamic acid produces colitis independent of proinflammatory eicosanoids while eicosanoid release could contribute to colitis produced by n-formyl-methionyl-leucyl-phenylalanine methyl ester. This experimental model of colitis may reflect one possible etiology of inflammatory bowel disease in humans, when bacterial chemotactic peptides breach mucosal defenses in susceptible individuals.

Animals↗
PubMed1990

Oxygen-dependent up-regulation of mucoid exopolysaccharide (alginate) production in Pseudomonas aeruginosa.

We previously showed substantial differences in Pseudomonas aeruginosa exopolysaccharide production in vitro at oxygen tensions reflective of the right versus left cardiac circuits in vivo (40 versus 80 mm Hg, respectively; A. S. Bayer, T. O'Brien, D. C. Norman, and C. C. Nast, J. Antimicrob. Chemother. 23:21-35, 1989). However, those studies did not specifically confirm this exopolysaccharide to be the characteristic P. aeruginosa mucoid alginate seen in patients with cystic fibrosis. With a murine monoclonal antibody prepared against P. aeruginosa alginate, strongly positive immunofluorescence (IF) staining of a nonmucoid P. aeruginosa strain (PA-96) was seen after its exposure in vitro to oxygen tensions (pO2) of approximately 80 mm Hg; the intensity of the IF staining under these conditions was similar to that observed with a phenotypically mucoid P. aeruginosa strain (C1712M) from a cystic fibrosis patient. In contrast, the same nonmucoid strain (PA-96), after exposure to pO2 of approximately 40 mm Hg, showed little IF staining for alginate. Following enzyme treatment with alginase, PA-96 cells previously exposed to the higher pO2 and exhibiting enhanced alginate production, as determined by IF staining, now showed no IF staining. Moreover, treatment of the oxygen-up-regulated PA-96 cells with alginase released amounts of unsaturated alginate breakdown products (uronic acids) quantitatively similar to those released by typically mucoid strains treated with the same enzyme. These data indicated that the P. aeruginosa exopolysaccharide in our studies was, indeed, mucoid alginate and that variations in oxygen tensions represent one of the trigger mechanisms for the up-regulation of mucoid exopolysaccharide production.

Fluorescent Antibody Technique↗
PubMed1990

Interleukin 1 suppresses inflammation in rabbit colitis. Mediation by endogenous prostaglandins.

Pretreatment with low-dose IL-1 has protective effects in animal models of inflammation or tissue injury, but the mechanisms of these protective effects are not established. To determine if prostaglandins are involved, we administered human recombinant IL-1 beta and measured rectal PGE2 production in rabbits with formalin-immune complex colitis. IL-1 beta (0.3 micrograms/kg) administered 24 h before induction of colitis increased PGE2 (231 +/- 36 to 1,299 +/- 572 pg/ml, P less than 0.01) and reduced subsequent inflammatory cell infiltration index (from 2.8 +/- 0.3 to 1.4 +/- 0.3, P less than 0.02) and edema (from 2.5 +/- 0.3 to 1.3 +/- 0.3, P less than 0.01) compared with vehicle-matched animals. Administration of ibuprofen (10 mg/kg i.v.) together with IL-1 beta prevented the stimulation of PGE2 and the reduction in inflammation. Colonic PGE2 production correlated inversely with subsequent severity of inflammation (P less than 0.02, r = -0.39) and edema (P less than 0.04, r = -0.35). IL-1-administration 30 min before induction of colitis did not affect the severity of inflammation. Similarly, pretreatment with a noninflammatory synthetic peptide (fragment 163-171) of human IL-1 beta, either 30 min or 24 h before colitis induction, did not reduce inflammation or increase prostaglandin synthesis. These data demonstrate that pretreatment with IL-1 beta 24 h before the induction of colitis reduces inflammation by a mechanism that requires prostaglandin synthesis.

Animals↗
PubMed1990

Interleukin 1 (IL-1) gene expression, synthesis, and effect of specific IL-1 receptor blockade in rabbit immune complex colitis.

Interleukin 1 (IL-1) may be a key mediator of inflammation and tissue damage in inflammatory bowel disease (IBD). In rabbits with immune complex-induced colitis, IL-1 alpha and beta mRNA levels were detectable at 4 h, peaked at 12 but were absent at 96 h after the induction of colitis. Colonic IL-1 tissue levels were measured by specific radioimmunoassays. IL-1 alpha was significantly elevated at 4 h (9.4 +/- 1.5 ng/g colon), progressively increased at 48 h (31 +/- 5.8 ng/g) and then decreased by 96 h (11.5 +/- 3.4 ng/g). IL-1 beta levels were 2.0 +/- 0.5 ng/g colon at 4 h, 5.0 +/- 1.6 ng/g at 48 h and undetectable by 96 h. By comparison, colonic levels of PGE2 and LTB4 were unchanged during the first 12 h and did not become elevated until 24 h. IL-1 alpha levels were highly correlated with inflammation (r = 0.885, P less than 0.0001), edema (r = 0.789, P less than 0.0001) and necrosis (r = 0.752, P less than 0.0005). Treatment with a specific IL-1 receptor antagonist (IL-1 ra) before and during the first 33 h after the administration of immune complexes markedly reduced inflammatory cell infiltration index (from 3.2 +/- 0.4 to 1.4 +/- 0.3, P less than 0.02), edema (from 2.2 +/- 0.4 to 0.6 +/- 0.3, P less than 0.01) and necrosis (from 43 +/- 10% to 6.6 +/- 3.2%, P less than 0.03) compared to vehicle-matched colitis animals. These studies demonstrate that (a) IL-1 gene expression and synthesis occur early in the course of immune complex-induced colitis; (b) are significantly elevated for 12 h before the appearance of PGE2 and LTB4; (c) tissue levels of IL-1 correlate with the degree of tissue inflammation and; (d) specific blockade of IL-1 receptors reduces the inflammatory responses associated with experimental colitis.

Antigen-Antibody Complex↗
PubMed1990

Intravegetation antimicrobial distribution in aortic endocarditis analyzed by computer-generated model. Implications for treatment.

The distribution of antibiotics into cardiac valvular tissues is incompletely understood. By integrative computer modeling, we have used previously obtained pharmacokinetic data in experimental endocarditis to characterize aminoglycoside distribution within various geographic sectors of aortic vegetations of rabbits and humans in the current study. In rabbits with pseudomonal aortic endocarditis receiving a standard regimen of amikacin (15 mg/kg every eight hours), sub-MBC levels of the drug for the infecting organism were calculated in the center of 0.38-cm vegetations; this occurred despite supra-MBC levels calculated in plasma and more peripheral loci of the vegetation. In contrast, with a high-dose regimen of amikacin (40 mg/kg every eight hours), supra-MBC drug levels were calculated throughout the entire vegetation for at least 50 percent of the dosing interval. Using similar computer-generated approaches, these data in the rabbit were approximately in simulated aminoglycoside penetration of 10-mm human aortic vegetations. Aminoglycoside regimens designed to yield supra-MBC serum levels in both normal and rapid drug eliminators consistently achieved sub-MBC levels in the center of the vegetation. Computer simulations also confirmed that daily doses of aminoglycoside at least two to four times higher than those ordinarily recommended are necessary to consistently achieve uniform supra-MBC intravegetation levels for an entire dosing interval. Such computer-generated data support the concept of maldistribution of aminoglycosides in aortic endocarditis and provide a rationale for investigating the use of high-dose regimens of aminoglycoside in treating experimental endocarditis.

Amikacin↗