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-or (TNF). Naive (neutrophil-replete) or neutropenic rats were infected with 10(7) yeast-phase CA; subgroups received GM-CSF (25 mu g/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)/mu l, mean +/- SE, vs. 3.7 +/- 0.4 x 10(3)/mu l, respectively, P < 0.01). Neutropenic rats given NS (baseline PMN = 41 +/- 10 mu l, 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/mu l, 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. Compared with baseline, TNF in serum and BALF did not differ within or among groups at any timepoints, regardless of CY or GM-CSF. Thus GM-CSF reduces lung injury and mortality during otherwise lethal candidiasis in the neutropenic host, despite minimal effects on circulating PMNs or on expression of TNF, a cytokine considered critical to host defense homeostasis.