Efficacy of LL-37 and granulocyte colony-stimulating factor in a neutropenic murine sepsis due to Pseudomonas aeruginosa.
A promising therapeutic strategy for the management of severe Pseudomonas infection in neutropenic patients may result from the coadministration of colony-stimulating factors (CSFs) that help maintain immune competence and antimicrobial peptides, a novel generation of adjunctive therapeutic agents with antimicrobial and anti-inflammatory properties. A promising peptide with these properties is LL-37, the only member of the cathelicidin family of antimicrobial peptides found in humans. BALB/c male mice were rendered neutropenic by intraperitoneal administration of cyclophosphamide on days -4 and -2 preinfection. Septic shock was induced at time 0 by intraperitoneal injection of 2x10 colony-forming units of P. aeruginosa American Type Culture Collection (ATCC) 27853. All animals were randomized to receive intravenously isotonic sodium chloride solution, 1 mg/kg of LL-37, 20 mg/kg of imipenem, 0.1 mg/kg of granulocyte CSF (G-CSF), 1 mg/kg of LL-37+0.1 mg/kg of G-CSF, or 20 mg/kg of imipenem+0.1 mg/kg of G-CSF. Lethality and bacterial growth in blood, peritoneum, spleen, liver, and kidney were evaluated. All regimens were significantly superior to controls at reducing the mouse lethality rate and bacterial burden in organs. Particularly, the combination between LL-37 and G-CSF was the most effective in protecting neutropenic mice from the onset of sepsis and in vitro significantly reduced the apoptosis of neutrophils. Combination therapy between LL-37 and G-CSF is a promising therapeutic strategy for the management of severe Pseudomonas infection complicated by neutropenia.
Cirioni
Oscar
O
Institute of Infectious Diseases and Public Health, Department of General Surgery, I.N.R.C.A. I.R.R.C.S.-Universita Politecnica delle Marche, Ancona, Italy. anconacmi@interfree.it
Ghiselli
Roberto
R
Tomasinsig
Linda
L
Orlando
Fiorenza
F
Silvestri
Carmela
C
Skerlavaj
Barbara
B
Riva
Alessandra
A
Rocchi
Marco
M
Saba
Vittorio
V
Zanetti
Margherita
M
Scalise
Giorgio
G
Giacometti
Andrea
A
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D023181:Antimicrobial Cationic Peptides / Q000494:pharmacology*; D017209:Apoptosis; D054804:Cathelicidins; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009503:Neutropenia / Q000097:blood* / Q000382:microbiology; D009504:Neutrophils / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry; D011552:Pseudomonas Infections / Q000378:metabolism* / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000378:metabolism*; D018805:Sepsis / Q000378:metabolism* / Q000382:microbiology*
D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D054804:Cathelicidins; D010455:Peptides; D016179:Granulocyte Colony-Stimulating Factor