title: Effects of Cl2MDP-encapsulating liposomes in a murine model of Pseudomonas aeruginosa-induced sepsis.
abstract: Pseudomonas aeruginosa is a pathogen that frequently causes acute lung injury, bacteremia and sepsis in critically ill patients. As tissue macrophages are a major producer of inflammatory mediators that contribute to septic physiology, and are essential for eliminating bacteria from the circulation, we investigated the role of tissue macrophages in the generation of both inflammatory and anti-inflammatory cytokines in septic shock by using our mouse model of P. aeruginosa pneumonia. To see the effects of tissue macrophage depletion, we intravenously injected dichloromethylene-diphosphonate (Cl2MDP)-encapsulating liposomes in mice. Two days after the liposome injection, we instilled cytotoxic P. aeruginosa (PA103) into the lung that disseminates and causes septic shock. After the infection, we collected blood and bronchoalveolar lavage fluids. The samples were then analyzed for TNF-alpha, MIP-2, and IL-10 concentration. We compared these results to control mice that received either liposomes without Cl2MDP or phosphate buffered saline alone. Plasma TNF-alpha, MIP-2, and IL-10 levels were significantly decreased in the tissue macrophage-depleted mice compared to the control groups of mice. Although depletion of tissue macrophages by Cl2MDP-liposome administration did not affect the severity of bacteremia or the survival of infected mice, these results imply that tissue macrophages have a major role in the production of both proinflammatory and anti-inflammatory cytokines in the circulation and in the causing septic physiology associated with P. aeruginosa pneumonia.
authors.affiliation: Department of Anesthesia and Perioperative Care, University of California, San Francisco, CA 94143-0542, USA.
authors.forename: Junichi
authors.initials: J
authors.lastname: Fujimoto
authors.forename: Jeanine P
authors.initials: JP
authors.lastname: Wiener-Kronish
authors.forename: Satoru
authors.initials: S
authors.lastname: Hashimoto
authors.forename: Teiji
authors.initials: T
authors.lastname: Sawa
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D054426:Chemokine CXCL2; D018925:Chemokines / Q000097:blood; D004002:Clodronic Acid / Q000008:administration & dosage / Q000494:pharmacology*; D016753:Interleukin-10 / Q000097:blood; D008081:Liposomes; D008264:Macrophages / Q000187:drug effects; D016676:Macrophages, Alveolar / Q000187:drug effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011552:Pseudomonas Infections; D011550:Pseudomonas aeruginosa; D012772:Shock, Septic / Q000382:microbiology*; D013047:Specific Pathogen-Free Organisms; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
chemical_list: D054426:Chemokine CXCL2; D018925:Chemokines; C404915:Cxcl2 protein, mouse; D008081:Liposomes; D014409:Tumor Necrosis Factor-alpha; D004002:Clodronic Acid; D016753:Interleukin-10