Recombinant GM-CSF reduces lung injury and mortality during neutropenic Candida sepsis.
Cyclophosphamide (CY)-induced neutropenia exacerbates septic shock and acute lung injury during Candida albicans (CA) fungemia in conscious rats. We hypothesized that treatment of such animals with recombinant murine granulocyte-macrophage colony-stimulating factor (GM-CSF) improves host defense during disseminated candidiasis by increasing peripheral neutrophils (PMNs) and enhancing endogenous production of antifungal cytokines including tumor necrosis factor-alpha (TNF). Naive (neutrophil-replete) or neutropenic rats were infected with 10(7) yeast-phase CA; subgroups received GM-CSF (25 micrograms/kg sc) or sterile 0.9% NaCl (NS) twice a day beginning 3 days before CA infection. Arterial hemodynamics, formed blood elements, bioactive TNF in serum and bronchoalveolar lavage fluid (BALF), and lung histopathology were monitored for up to 72 h after infection. All naive animals receiving GM-CSF (n = 5) and 78% of naive rats given NS (n = 9) remained normotensive through 72 h with no lung injury, differing principally in baseline PMNs before CA infection (8.8 +/- 1.8 x 10(3)/microliters, mean +/- SE, vs. 3.7 +/- 0.4 x 10(3)/microliters, respectively, P < 0.01). Neutropenic rats given NS (baseline PMN = 41 +/- 10/microliters, n = 7) were sensitized to CA, and 100% died of hypothermic shock with severe respiratory distress within 56 h of infection. Pulmonary periarterial and alveolar hemorrhage were prominent. Although GM-CSF did not increase baseline PMNs in CY animals by the outset of infection (162 +/- 58/microliters, n = 8), 62% of these rats remained normotensive and eupneic through 72 h (P < 0.01), and their lungs showed no perivascular hemorrhage, alveolar disruption, or fungi.(ABSTRACT TRUNCATED AT 250 WORDS)
Lechner
A J
AJ
Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, Missouri.
Lamprech
K E
KE
Potthoff
L H
LH
Tredway
T L
TL
Matuschak
G M
GM
D000818:Animals; D001794:Blood Pressure; D002176:Candida albicans / Q000302:isolation & purification; D002177:Candidiasis / Q000473:pathology* / Q000503:physiopathology / Q000628:therapy; D016469:Fungemia / Q000473:pathology* / Q000503:physiopathology / Q000628:therapy; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology; D008172:Lung Diseases, Fungal / Q000473:pathology* / Q000503:physiopathology / Q000628:therapy; D008297:Male; D009503:Neutropenia / Q000209:etiology / Q000503:physiopathology / Q000628:therapy*; D011674:Pulse; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D012119:Respiration
D011994:Recombinant Proteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor