title: Synergistic septicemic action of the gram-positive bacterial cell wall components peptidoglycan and lipoteichoic acid in the pig in vivo.
abstract: Despite the fact that gram-positive infections constitute around 50% of all cases leading to septic shock, little is yet known about the mechanisms involved. This study was carried out to find out more about the effects of cell wall components peptidoglycan (PepG) and lipoteichoic acid (LTA) of the gram-positive bacterium Streptococcus pyogenes in the pig. Specific pathogen-free pigs (20 kg bodyweight) were pretreated with metyrapone (a cortisol-synthesis inhibitor) and then were given 2-h infusions of 160 microg/kg of PepG (n = 5), 160 microg/kg LTA (n=5), or a combination of both (LTA + PepG, 160 microg/kg each, n = 5). Four hours after start of the infusions, the PepG, LTA, and LTA + PepG groups showed decreases in mean arterial pressure (change of -11%, -25%, and -47% from baseline, respectively), dynamic lung compliance (-18%, -24%, and -38%), arterial oxygen tension (-10%, -16%, and -37%), changes in blood leukocyte numbers (+11%, -27%, and -67%), and increases in pulmonary vascular resistance index (+7%, +106%, and +307% from baseline) and metabolic acidosis (base excess values decreased with 1.8, 2.3 and 8.1 units). The differences between the PepG and LTA + PepG groups were statistically significant (P < 0.05, Kruskal-Wallis tests), but not between LTA and LTA + PepG groups. However, no changes in systemic nitric oxide (NO) production could be detected, which is much in contrast to studies on lower order animals. Moreover, comparison of the results obtained using this model with those obtained in a model of endotoxin-induced septic shock showed distinct difference in the mechanisms by which gram-positive and gram-negative bacterial components exert their actions. For example, a marked fall in systemic blood pressure and dynamic lung compliance is seen in both models, but in the present gram-positive sepsis model, much less interleukin-8 and tumor necrosis factor-alpha are produced. In conclusion, this study showed that PepG and LTA act synergistically to cause respiratory failure and septic shock in the pig. The infusion of the combination of PepG and LTA in the pig could serve as a new, well-controlled model for studies of gram-positive sepsis.
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: R J
authors.initials: RJ
authors.lastname: Middelveld
authors.forename: K
authors.initials: K
authors.lastname: Alving
mesh_terms: D000818:Animals; D004357:Drug Synergism; D019332:Endothelin-1 / Q000097:blood; D004731:Endotoxins / Q000633:toxicity; D005260:Female; D006854:Hydrocortisone / Q000097:blood; D016209:Interleukin-8 / Q000097:blood; D007958:Leukocyte Count; D008070:Lipopolysaccharides / Q000633:toxicity*; D008170:Lung Compliance / Q000187:drug effects; D008297:Male; D008797:Metyrapone / Q000494:pharmacology; D009569:Nitric Oxide / Q000032:analysis; D010100:Oxygen / Q000097:blood; D010457:Peptidoglycan / Q000633:toxicity*; D011652:Pulmonary Circulation / Q000187:drug effects; D018805:Sepsis / Q000097:blood / Q000503:physiopathology*; D012772:Shock, Septic / Q000503:physiopathology; D013047:Specific Pathogen-Free Organisms; D013297:Streptococcus pyogenes; D013552:Swine; D013682:Teichoic Acids / Q000633:toxicity*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis; D014655:Vascular Resistance / Q000187:drug effects
chemical_list: D019332:Endothelin-1; D004731:Endotoxins; D016209:Interleukin-8; D008070:Lipopolysaccharides; D010457:Peptidoglycan; D013682:Teichoic Acids; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; C009900:lipoteichoic acid; D010100:Oxygen; D006854:Hydrocortisone; D008797:Metyrapone