Inhalation of low-dose endotoxin favors local T(H)2 response and primes airway phagocytes in vivo.
BACKGROUND
We previously reported that inhalation of 5 mug of endotoxin (30,000 endotoxin units [EU]) induced airway neutrophilia and decreased phagocytosis by airway monocytes, macrophages, and neutrophils. Conversely, we recently reported that very low doses of endotoxin, which are not associated with neutrophil influx, enhance response to allergen in the nasal and bronchial airway.


OBJECTIVE
We sought to determine whether endotoxin (0-10,000 EU) at doses that do not induce airway neutrophilia prime airway phagocyte function, alter expression of relevant cell-surface receptors (membrane-bound CD14 [mCD14] and CD11b/CR3), and cause induction of a T(H)2 cytokine profile in the airway.


METHODS
Thirteen nonallergic healthy volunteers were challenged on separate occasions with escalating doses of Clinical Center Reference Endotoxin (CCRE; 0, 2500, 5000, and 10,000 EU), with 9 volunteers completing the entire dose range. Sputum cells and fluid-phase components were recovered 6 hours after challenge. Sputum inflammatory cells were analyzed by means of flow cytometry for mCD14 and CD11b expression and immune function (phagocytosis of IgG-opsonized zymosan particles).


RESULTS
At all doses of CCRE, there was no increase in airway neutrophils relative to that caused by saline. However, inhalation of 10,000 EU enhanced phagocytosis (monocytes and macrophages), upregulated expression of CD11b and mCD14 (monocytes and neutrophils), and increased IL-13 levels, whereas IFN-gamma levels were significantly decreased.


CONCLUSIONS
The 10,000-EU dose of CCRE is subthreshold for inducing airway neutrophilia but primes phagocyte function and cell-surface receptor expression in the presence of increased IL-13 and decreased IFN-gamma levels. We speculate that low-dose endotoxin challenge skews airway inflammation in a T(H)2 direction in vivo .
Alexis
Neil E
NE
UNC School of Medicine, UNC Chapel Hill, Chapel Hill, NC 27599, USA. Neil_Alexis@med.unc.edu
Lay
John C
JC
Almond
Martha
M
Peden
David B
DB
D000280:Administration, Inhalation; D000293:Adolescent; D000328:Adult; D016207:Cytokines / Q000096:biosynthesis; D004731:Endotoxins / Q000008:administration & dosage*; D006801:Humans; D008168:Lung / Q000502:physiology; D008875:Middle Aged; D009504:Neutrophils / Q000502:physiology; D010587:Phagocytosis / Q000187:drug effects*; D018418:Th2 Cells / Q000276:immunology*
D016207:Cytokines; D004731:Endotoxins