Immunomodulation in the critically ill
ABSTRACT Immunotherapy in the critically ill is an appealing notion because of the apparent abnormal immune and inflammatory responses seen in so many patients. The administration of a medication that could alter immune responses and decrease mortality in patients with sepsis could represent a 'magic bullet'. Various approaches have been tried over the last 20 yr: steroids; anti-endotoxin or anti-cytokine antibodies; cytokine receptor antagonists; and other agents with immune-modulating side-effects. However, in some respects, research along these lines has been unsuccessful or disappointing at best. The current state of knowledge is summarized with particular reference to sepsis and the acute respiratory distress syndrome.
SourceAvailable from: PubMed Central[Show abstract] [Hide abstract]
ABSTRACT: Aim:The receptor of advanced glycation end products (RAGE) participates in a variety of pathophysiological processes and inflammatory responses. The aim of this study was to investigate the therapeutic potential of an anti-RAGE neutralizing antibody for severe thermal injury in rats, and to determine whether the treatment worked via modulating cellular immune function.Methods:Full-thickness scald injury was induced in Wistar rats, which were treated with the anti-RAGE antibody (1 mg/kg, iv) at 6 h and 24 h after the injury. The rats were sacrificed on d 1, 3, 5, and 7. Blood and spleen samples were harvested to monitor organ function and to analyze dendritic cell (DC) and T cell cytokine profiles. The survival rate was analyzed up to d 7 after the injury.Results:Administration of the antibody significantly increased the 7 d survival rate in thermally injured rats (6.67% in the model group; 33.33% in anti-RAGE group). Treatment with the antibody also attenuated the multiple organ dysfunction syndrome (MODS) following the thermal injury, as shown by significant decreases in the organ dysfunction markers, including serum ALT, AST, blood urea nitrogen, creatinine and CK-MB. Moreover, treatment with the antibody significantly promoted DC maturation and T cell activation in the spleens of thermally injured rats.Conclusion:Blockade of the RAGE axis by the antibody effectively ameliorated MODS and improved the survival rate in thermally injured rats, which may be due to modulation of cellular immune function.Acta Pharmacologica Sinica 08/2014; 35(9). DOI:10.1038/aps.2014.56 · 2.50 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: IntroductionThe pathophysiology of endotoxemia-induced acute kidney injury (AKI) is characterized by an intense activation of the host immune system and renal resident cells by lipopolysaccharide (LPS) and derived pro-inflammatory products. However, the occurrence of renal fibrosis in this setting has been poorly investigated. The aim of the present study was to investigate the possible association between endothelial dysfunction and acute development of tissue fibrosis in a swine model of LPS-induced AKI. Moreover we studied the possible effects of coupled plasma filtration adsorption (CPFA) in this setting.Methods After 9 h from LPS infusion and 6 h of CPFA treatment, histological and biochemical changes were analyzed in pigs. Apoptosis and endothelial dysfunction were assessed on renal biopsies. The levels of LPS binding protein (LBP) were quantified by ELISA. Endothelial cells (EC) were stimulated in vitro with LPS and cultured in the presence of swine sera and were analyzed by FACS and Real time RT-PCR.ResultsIn a swine model of LPS-induced AKI, we observed that acute tubulointerstitial fibrosis occurred within 9 h from LPS injection. Acute fibrosis was associated with dysfunctional alpha-smooth muscle actin (¿-SMA)+ EC characterized by active proliferation (Ki-67+) without apoptosis (Caspase-3-). In accordance, LPS led to EC dysfunction in vitro with significant Vimentin and N-cadherin expressions and increased collagen I mRNA synthesis. Therapeutic intervention by citrate-based CPFA significantly prevented acute fibrosis in endotoxemic animals, by preserving EC phenotype both in peritubular capillaries and renal arteries. We found that the removal of LBP from plasma was crucial to eliminate the effects of LPS on EC dysfunction, by blocking LPS-induced collagen I production.Conclusions Our data indicates that EC dysfunction might be pivotal in the acute development of tubulointerstitial fibrosis in LPS-induced AKI. Selective removal of the LPS adaptor protein LBP might represent a future therapeutic option to prevent EC dysfunction and tissue fibrosis in endotoxemia-induced AKI.Critical care (London, England) 09/2014; 18(5):520. DOI:10.1186/s13054-014-0520-2
[Show abstract] [Hide abstract]
ABSTRACT: Objective: To determine whether vitamin D levels correlate with procalcitonin (PCT) levels and mortality in septic patients. Methods: The following data were collected from 236 patients upon admission to intensive care units (ICUs): demographics; Acute Physiology and Chronic Health Evaluation (APACHE) II score; Sequential Organ Failure Assessment (SOFA) score; 25-hydroxyvitamin D (25OHD), PCT, intact parathyroid hormone (PTH), albumin, creatinine, and ionized calcium (iCa) levels; 25OHD sampling seasonality; fluid load (colloid and crystalloid before 25OHD sampling); mechanical ventilation duration; and length of ICU stay (LOS). The primary end point was all-cause mortality 28 days after ICU admission. Results: Patients with 25OHD deficiency had significantly higher APACHE II and SOFA scores, positive blood culture rates, PCT levels, intact PTH levels, and 28-day mortality rates. These patients also had lower iCa levels, longer LOS, and longer ventilator times than patients with 25OHD insufficiency or sufficiency. Age, sex, 25OHD sampling seasonality, serum albumin and creatinine levels, and fluid load did not vary among the three groups. Serum 25OHD levels at admission were significantly negatively correlated with PCT levels. PTH responders had significantly higher 28-day mortality rates than did PTH nonresponders. Cox regression showed that 25OHD of <20 ng/mL was an independent risk factor for 28-day mortality. Conclusions: Lower serum 25OHD levels at ICU admission were associated with 28-day mortality in septic patients. Serum 25OHD levels were inversely correlated with PCT levels. Hypovitaminosis D was associated with higher mortality rates in PTH responders than in nonresponders.Journal of Clinical Endocrinology & Metabolism 11/2014; 100(2):jc20134330. DOI:10.1210/jc.2013-4330 · 6.31 Impact Factor