The local inflammatory responses to infection of the peritoneal cavity in humans: Their regulation by cytokines, macrophages, and other leukocytes

Studies on infection-induced inflammatory reactions in humans rely largely on findings in the blood compartment. Peritoneal leukocytes from patients treated with peritoneal dialysis offer a unique opportunity to study in humans the inflammatory responses taking place at the site of infection. Compared with peritoneal macrophages (pMφ) from uninfected patients, pMφ from infected patients display ex vivo an upregulation and downregulation of proinflammatory and anti-inflammatory mediators, respectively. Pro-IL-1β processing and secretion rather than synthesis proves to be increased in pMφ from infectious peritonitis suggesting up-regulation of caspase-1 in vivo. A crosstalk between pMφ, γδ T cells, and neutrophils has been found to be involved in augmented TNFα expression and production during infection. The recent finding in experimental studies that alternatively activated macrophages (Mφ2) increase by proliferation rather than recruitment may have significant implications for the understanding and treatment of chronic inflammatory conditions such as encapsulating peritoneal sclerosis (EPS). Copyrigh

Regulation of cytokine release from peritoneal macrophages of patients on continuous ambulatory peritoneal dialysis

The foundation of this thesis was laid in 1982 when we made the first studies of the production of inflammatory mediators by macrophages collected from effluent dialysate of patients on Continuous Ambulatory Dialysis (CAPD). During the frrst experiments, these cells, harvested from infection-free patients, proved to be suitable for immunopharmacological studies (4). When macrophages were collected when CAPD was complicated by an infectious peritonitis, the cells exhibited some striking differences in comparison with macrophages that were collected when the patients were infection-free. Notably the finding that the release of prostaglandins and the intracellular cAMP levels were decteased in macrophages collected during an episode of peritonitis, was intriguing (2). While prostaglandins are well known for their proinflammatory properties they can have antiinflammatory properties as well thought to be mediated by stimulating intracellular cAMP levels (3). At that time emphasis was put on the proinflammatory properties of prostaglandins, while the relevance of t.l:te antiinflammatory properties to in vivo conditions was sometimes questioned. Tne finding that macrophages from an inflammatory environment showed a decrease in the release of prostaglandins, might indicate, that prostaglandins fulfil antiinflammatory-immunomodulatory rather than proinflammatory functions with regard to these macrophages during the acute phase of an inflammation. A decrease in the release of the antiinflammatory prostaglandins could allow macrophages to become "activated" during an infection (7). To test this postulate I proposed, in 1983, to i..-tvestigate the secretion of the proinfla.'lliDatory "factor" later identified as interleukin-1: IL-l, by using peritoneal macrophages isolated from CAPD patients during peritoPitis and during an infection-free period. The following questions had to be answered: 1) Is the decreased secretion of the antii'l.flammatory prostaglandins, as found during peritonitis, associated with increased secretion of the proinflammatory IL-l? 2) Do prostaglandins have inhibitory effects on IL-l secretion? These questions underlie the studies of this thesis. IL-l secretion by peritoneal macrophages from infected patients as compared to infection-free patients, is described in chapter 5. In chapter 6, the relationship between the secretion of IL-lB and that of prostaglandins (PGEz, PGI:J was studied. In chapter 7, the in vitro secretion of Tumor Necrosis Factor ex (TNFcx), an other cytokine with proinflammatory properties, by peritoneal macrophages from infected patients is compared with that of infection-free patients. To what extent the release of IL-lB and TNFcx from peritoneal macrophages is affected by exogenous PGEz or the cyclooxygenase inhibitor indomethacin, is discussed in chapter 8. These findi.'l.gs are summa.Tized in chapter 9. Furthermore the relevance of these findings with regard to the acquisition of functional competence by peritoneal macrophages during infection, is discusse

Peritoneal Protein Losses and Cytokine Generation in Automated Peritoneal Dialysis with Combined Amino Acids and Glucose Solutions

Objectives. Protein-energy malnutrition as a consequence of deficient protein intake frequently occurs in peritoneal dialysis (PD) patients. Previously, we showed that peritoneal dialysate containing a mixture of amino acids (AA) and glucose has anabolic effects. However AA-dialysate has been reported to increase intraperitoneal protein and AA losses and the release of proinflammatory cytokines (interleukine-6 (IL-6) and tumor necrosis factor alpha (TNFα)). We investigated the effect of AA plus glucose (AAG) solutions on peritoneal protein losses and cytokine generation. Methods. In 6 patients on standard automated peritoneal dialysis (APD) 12 APD sessions of 6 cycles each were performed during the night using dialysate containing 1.1% AA plus glucose or glucose alone as control. Protein losses and TNFα and IL-6 concentrations were measured in dialysates separately collected from nightly cycling and daytime dwell. Results. The 24 hour-protein losses with AAG (median 6.7 g, range 4.7–9.4 g) were similar to control dialysate (median 6.0 g, range 4.2–9.2 g). Daytime dialysate IL-6 levels were higher after nightly AAG dialysis than after control dialysis (142 pg/ml and 82 pg/ml, respectively, P<.05). TNFα concentrations were very low. Conclusion. Nightly APD with amino acids containing dialysate was associated with an increase in peritoneal IL-6 generation during the day. The addition of AA to standard glucose dialysis solutions did not induce a significant increase of peritoneal protein losses

Continuous ambulatory peritoneal dialysis: pharmacokinetics and clinical outcome of paclitaxel and carboplatin treatment

Purpose: Administration of chemotherapy in patients with renal failure, treated with hemodialysis or continuous ambulatory peritoneal dialysis (CAPD) is still a challenge and literature data is scarce. Here we present a case study of a patient on CAPD, treated with weekly and three-weekly paclitaxel/ carboplatin for recurrent ovarian cancer. Experimental: During the first, second and ninth cycle of treatment, blood, urine and CAPD samples were collected for pharmacokinetic analysis of paclitaxel and total and unbound carboplatin-derived platinum. Results: Treatment was well tolerated by the patient. No excessive toxicity was observed and at the e

The Immune System in Stroke

Stroke represents an unresolved challenge for both developed and developing countries and has a huge socio-economic impact. Although considerable effort has been made to limit stroke incidence and improve outcome, strategies aimed at protecting injured neurons in the brain have all failed. This failure is likely to be due to both the incompleteness of modelling the disease and its causes in experimental research, and also the lack of understanding of how systemic mechanisms lead to an acute cerebrovascular event or contribute to outcome. Inflammation has been implicated in all forms of brain injury and it is now clear that immune mechanisms profoundly influence (and are responsible for the development of) risk and causation of stroke, and the outcome following the onset of cerebral ischemia. Until very recently, systemic inflammatory mechanisms, with respect to common comorbidities in stroke, have largely been ignored in experimental studies. The main aim is therefore to understand interactions between the immune system and brain injury in order to develop novel therapeutic approaches. Recent data from clinical and experimental research clearly show that systemic inflammatory diseases -such as atherosclerosis, obesity, diabetes or infection - similar to stress and advanced age, are associated with dysregulated immune responses which can profoundly contribute to cerebrovascular inflammation and injury in the central nervous system. In this review, we summarize recent advances in the field of inflammation and stroke, focusing on the challenges of translation between pre-clinical and clinical studies, and potential anti-inflammatory/immunomodulatory therapeutic approaches