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) impro ves host defense during disseminated candidiasis by increasing periphe ral neutrophils (PMNs) and enhancing endogenous production of antifung al cytokines including tumor necrosis factor-or (TNF). Naive (neutroph il-replete) or neutropenic rats were infected with 10(7) yeast-phase C A; 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 hemodynami cs, 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 7 8% of naive rats given NS (n = 9) remained normotensive through 72 h w ith no lung injury, differing principally in baseline PMNs before CA i nfection (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 h ypothermic shock with severe respiratory distress within 56 h of infec tion. Pulmonary periarterial and alveolar hemorrhage were prominent. A lthough GM-CSF did not increase baseline PMNs in CY animals by the out set 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 show ed no perivascular hemorrhage, alveolar disruption, or fungi. Compared with baseline, TNF in serum and BALF did not differ within or among g roups at any timepoints, regardless of CY or GM-CSF. Thus GM-CSF reduc es lung injury and mortality during otherwise lethal candidiasis in th e neutropenic host, despite minimal effects on circulating PMNs or on expression of TNF, a cytokine considered critical to host defense home ostasis.