chondroitin-sulfates and Pneumonia

During 2007 and 2008 it is likely that millions of patients in the US received heparin contaminated (CH) with oversulfated chondroitin sulfate, which was associated with anaphylactoid reactions. We tested the hypothesis that CH was associated with serious morbidity, mortality, intensive care unit (ICU) stay and heparin-induced thrombocytopenia following adult cardiac surgery.. We conducted a single center, retrospective, propensity-matched cohort study during the period of CH and the equivalent time frame in the three preceding or the two following years. Perioperative data were obtained from the institutional record of the Society of Thoracic Surgeons National Database, for which the data collection is prospective, standardized and performed by independent investigators. After matching, logistic regression was performed to evaluate the independent effect of CH on the composite adverse outcome (myocardial infarction, stroke, pneumonia, dialysis, cardiac arrest) and on mortality. Cox regression was used to determine the association between CH and ICU length of stay. The 1∶5 matched groups included 220 patients potentially exposed to CH and 918 controls. There were more adverse outcomes in the exposed cohort (20.9% versus 12.0%; difference  =  8.9%; 95% CI 3.6% to 15.1%, P < 0.001) with an odds ratio for CH of 2.0 (95% CI, 1.4 to 3.0, P < 0.001). In the exposed group there was a non-significant increase in mortality (5.9% versus 3.5%, difference = 2.4%; 95% CI, -0.4 to 3.5%, P  =  0.1), the median ICU stay was longer by 14.1 hours (interquartile range -26.6 to 79.8, S = 3299, P = 0.0004) with an estimated hazard ratio for CH of 1.2 (95% CI, 1.0 to 1.4, P = 0.04). There was no difference in nadir platelet counts between cohorts.. The results from this single center study suggest the possibility that contaminated heparin might have contributed to serious morbidity following cardiac surgery.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Cardiac Surgical Procedures; Chondroitin Sulfates; Drug Contamination; Female; Heart Arrest; Heparin; Humans; Intensive Care Units; Length of Stay; Logistic Models; Male; Middle Aged; Myocardial Infarction; Odds Ratio; Pneumonia; Renal Dialysis; Retrospective Studies; Risk Factors; Stroke; Survival Analysis

Disturbed alveolar fibrin turnover is a characteristic feature of pneumonia. Inhibitors of coagulation could exert lung-protective effects via anticoagulant (inhibiting fibrin deposition) and possibly anti-inflammatory pathways, but could also affect host defense. In this randomized controlled in vivo laboratory study, rats were challenged intratracheally with Pseudomonas aeruginosa, inducing pneumonia, and randomized to local treatment with normal saline (placebo), recombinant human activated protein C (rh-APC), plasma-derived antithrombin (AT), heparin, or danaparoid. Induction of P. aeruginosa pneumonia resulted in activation of pulmonary coagulation and inhibition of pulmonary fibrinolysis, as reflected by increased pulmonary levels of thrombin-AT complexes and fibrin degradation products and decreased pulmonary levels plasminogen activator activity. Pseudomonas aeruginosa pneumonia was accompanied by systemic coagulopathy, since systemic levels of thrombin-AT complexes increased, and systemic levels of plasminogen activator activity decreased. Although rh-APC and plasma-derived AT potently limited pulmonary coagulopathy, neither heparin nor danaparoid affected net pulmonary fibrin turnover. Recombinant human APC also displayed systemic anticoagulant effects. Neither bacterial clearance nor pulmonary inflammation was affected by anticoagulant therapy. Nebulization of rh-APC or plasma-derived AT attenuated pulmonary coagulopathy, but not bacterial clearance or inflammation, in a rat model of P. aeruginosa pneumonia.

Topics: Animals; Anticoagulants; Antithrombins; Blood Coagulation; Chondroitin Sulfates; Dermatan Sulfate; Fibrinolysis; Heparin; Heparitin Sulfate; Inflammation; Male; Pneumonia; Pseudomonas aeruginosa; Rats; Rats, Sprague-Dawley

Heparin is an excellent inhibitor of P- and L-selectin binding to the carbohydrate determinant, sialyl Lewis(x). As a consequence of its anti-selectin activity, heparin attenuates metastasis and inflammation. Here we show that fucosylated chondroitin sulfate (FucCS), a polysaccharide isolated from sea cucumber composed of a chondroitin sulfate backbone substituted at the 3-position of the beta-D-glucuronic acid residues with 2,4-disulfated alpha-L-fucopyranosyl branches, is a potent inhibitor of P- and L-selectin binding to immobilized sialyl Lewis(x) and LS180 carcinoma cell attachment to immobilized P- and L-selectins. Inhibition occurs in a concentration-dependent manner. Furthermore, FucCS was 4-8-fold more potent than heparin in the inhibition of the P- and L-selectin-sialyl Lewis(x) interactions. No inhibition of E-selectin was observed. FucCS also inhibited lung colonization by adenocarcinoma MC-38 cells in an experimental metastasis model in mice, as well as neutrophil recruitment in two models of inflammation (thioglycollate-induced peritonitis and lipopolysaccharide-induced lung inflammation). Inhibition occurred at a dose that produces no significant change in plasma activated partial thromboplastin time. Removal of the sulfated fucose branches on the FucCS abolished the inhibitory effect in vitro and in vivo. Overall, the results suggest that invertebrate FucCS may be a potential alternative to heparin for blocking metastasis and inflammatory reactions without the undesirable side effects of anticoagulant heparin.

Topics: Adenocarcinoma; Animals; Anticoagulants; Carbohydrate Conformation; Cell Adhesion; Chondroitin Sulfates; Disease Models, Animal; Dose-Response Relationship, Drug; Heparin; L-Selectin; Lipopolysaccharides; Lung Neoplasms; Mice; Neoplasm Metastasis; Neoplasms, Experimental; Neutrophil Infiltration; P-Selectin; Partial Thromboplastin Time; Peritonitis; Pneumonia; Sea Cucumbers; Thioglycolates

Intratracheal instillation of bleomycin in hamsters initiates a series of events that mimic human interstitial pulmonary fibrosis. Because glycosaminoglycans and particularly hyaluronan (hyaluronic acid, HA), may play an important role in the extracellular matrix response to early injury and subsequent fibrosis, this study was undertaken to define the early time course of changes in HA and hyaluronidase. Hamsters were given either 1 unit bleomycin sulfate in 0.2 ml saline or 0.2 ml saline (control), and randomly selected animals from both groups were killed at Days 3, 5, 6, 7, 9, and 17. Glycosaminoglycan fractions prepared from lung tissue of individual animals were analyzed for HA. The maximal HA content was reached 6 days after instillation of bleomycin and was 14.6-fold the normal value. The weight of injured lungs was 2.3-fold the control value. Thus, the increase in HA content was 30-fold. By Day 7 the HA content had dropped sharply. It then declined gradually to approximately double control values at Day 17. The specific activity of lysosomal hyaluronidase was the same in bleomycin-treated lungs and control lungs. Total units of the enzyme were increased in injured lungs, even at the time of maximal HA content, indicating active turnover of HA. The maximal HA content occurs prior to the rise in collagen and elastin biosynthesis. This observation in addition to the magnitude of the increase and its abrupt decline suggest that HA may be an important initiating factor for pathologic changes in lung extracellular matrix components.

Topics: Animals; Bleomycin; Chondroitin Sulfates; Cricetinae; Dermatan Sulfate; Female; Hyaluronic Acid; Hyaluronoglucosaminidase; Lung; Mesocricetus; Organ Size; Pneumonia; Pulmonary Alveoli; Time Factors

Pretreatment of the lung graft with concanavalin A (Con A) or chondroitin sulfate (CIS) was used to modify the lung allograft response after transplantation into moderately immunosuppressed (low doses of azathioprine and prednisone) recipients. Significant (p less than 0.05) prolongation of survival was observed after graft pretreatment. Pneumonia and rejection were the most frequent causes of death for all groups of dogs. However, only 3 out of 6 animals from each of the groups with pretreated grafts died of pneumonia or rejection, whereas 5 of the 6 animals in the control group died of these causes. Furthermore, when rejection occurred in the dogs with lung grafts pretreated with Con A or CIS, it was considerably delayed compared with the controls. Partial pressure of arterial oxygen, chest roentgenograms, and lung histology were good indicators of lung viability after transplantation.

Topics: Animals; Chondroitin; Chondroitin Sulfates; Concanavalin A; Dogs; Female; Graft Rejection; Lung; Lung Transplantation; Male; Pneumonia; Postoperative Complications; Radiography; Transplantation, Homologous