title: Protamine sulfate reduces the susceptibility of thermally injured mice to Pseudomonas aeruginosa infection.
abstract: BACKGROUND
  In this study, we investigated the ability of protamine sulfate, at sub-bactericidal dosing, to interfere with the in vivo virulence of Pseudomonas aeruginosa (PAO1) during burn wound infection.
  
  
  METHODS
  The study was conducted using the murine model of thermal injury. Preliminary experiments determined a protocol for administration of protamine sulfate that had no in vivo bactericidal effects. Based on this, the effect of local injection of protamine sulfate on the in vivo virulence of PAO1 was assessed using these parameters: (1) the percent mortality among PAO1-infected, thermally injured mice; (2) the local proliferation and spread of PAO1 within the infected burned tissue; (3) the systemic spread of PAO1 within thermally injured/infected mice; and (4) the local cytokine response elicited by PAO1 thermally injured/infected mice.
  
  
  RESULTS
  Injection of protamine sulfate into the thermally injured tissue of PAO1-infected/thermally injured mice significantly decreased the percent mortality and inhibited the systemic dissemination of PAO1 microorganisms to the liver and spleen. It had no effect, however, on the ability of the bacteria to proliferate and spread within the thermally injured tissue. It also was determined that protamine sulfate was ineffective at preventing mouse death at the dose administered if injected intramuscularly instead of directly into burned tissue. Protamine sulfate reduced the expression of the proinflammatory cytokines IL-6 and LIF in the injured/infected tissue. Heparan sulfate given in conjunction with protamine sulfate returned mortality levels to those of untreated mice.
  
  
  CONCLUSIONS
  Our results suggest that: (1) local injection of sub-bactericidal doses of protamine sulfate reduces the virulence of P. aeruginosa; (2) this effect is due to interference with the systemic rather than local spread of P. aeruginosa; and (3) local application of protamine sulfate may have potential as supportive therapy for prevention of systemic P. aeruginosa infection in severely burned patients.
authors.affiliation: University of Washington Health Sciences Center, 1959 NE Pacific St., Seattle, WA 98195, USA.
authors.forename: Allan
authors.initials: A
authors.lastname: Haynes
authors.forename: Kendra P
authors.initials: KP
authors.lastname: Rumbaugh
authors.forename: Pyong Woo
authors.initials: PW
authors.lastname: Park
authors.forename: Abdul N
authors.initials: AN
authors.lastname: Hamood
authors.forename: John A
authors.initials: JA
authors.lastname: Griswold
mesh_terms: D000818:Animals; D002056:Burns / Q000382:microbiology*; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D004198:Disease Susceptibility; D004305:Dose-Response Relationship, Drug; D005260:Female; D006497:Heparan Sulfate / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000502:physiology; D051379:Mice; D011479:Protamines / Q000494:pharmacology*; D011509:Proteoglycans / Q000502:physiology; D011552:Pseudomonas Infections / Q000517:prevention & control*; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000472:pathogenicity; D053667:Syndecans; D014774:Virulence
chemical_list: D016207:Cytokines; D006497:Heparan Sulfate; D008562:Membrane Glycoproteins; D011479:Protamines; D011509:Proteoglycans; D053667:Syndecans