Granulocyte-macrophage colony-stimulating factor amplifies lipopolysaccharide-induced bronchoconstriction by a neutrophil- and cyclooxygenase 2-dependent mechanism
L. Wollin et al., Granulocyte-macrophage colony-stimulating factor amplifies lipopolysaccharide-induced bronchoconstriction by a neutrophil- and cyclooxygenase 2-dependent mechanism, AM J R CRIT, 163(2), 2001, pp. 443-450
Granulocyte-macrophage colony-stimulating factor (CM-CSF) is used to amelio
rate neutropenia in patients after antineoplastic treatment. It has also be
en suggested as an adjunct treatment in septic patients; however, the recru
itment and priming of leukocytes by CM-CSF bears the hazard of a hyperinfla
mmatory response. In particular, the role of CM-CSF in pulmonary functions
in septic lungs is still unclear. Therefore, we pretreated rats in vivo wit
h CM-CSF (50 mug/kg, intravenous) and assessed the pulmonary functions of t
heir subsequently prepared isolated perfused lungs when exposed to subtoxic
concentrations of lipopolysaccharide (LPS, 2 mug/ml), These lungs showed e
nhanced expression of cy clooxygenase 2 (COX-2), a significant increase in
thromboxane (TX) and tumor necrosis factor (TNF) release into the venous pe
rfusate, and bronchoconstriction. COX-2 inhibition or blocking of the TX re
ceptor abolished the CM-CSF/LPS-induced bronchoconstriction, but not the TN
F release. Neutralizing antibodies against TNF did not prevent CM-CSF/LPS-i
nduced bronchoconstriction. After CM-CSF pretreatment, massive neutrophil i
nvasion into the lung occurred. Neutropenic rats were protected against CM-
CSF/LPS-induced lung injury. Similar results were obtained in rats pretreat
ed with C-CSF instead of CM-CSF. We conclude that GM-CSF pretreatment exace
rbates pulmonary injury by low-dose LPS via COX-2 expression, TX release, a
nd bronchoconstriction by initiating neutrophil invasion and activation.