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* Department of Pharmacology, Almirall Prodesfarma Research Center, Barcelona, Spain; and
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109
The mechanistic relationships between initiating stimulus, cellular
source and sequence of chemokine expression, and leukocyte recruitment
during inflammation are not clear. To study these relationships in an
acute inflammatory process, we challenged a murine air pouch with
carrageenan. A time-dependent increase in TNF-
, monocyte
chemottractant protein-1 (MCP-1), macrophage-inflammatory protein-1
(MIP-1
), RANTES, KC, and MIP-2 was found in the exudates
preceding cell recruitment, but displaying different kinetic profiles.
Air pouches generated for 2, 6, or 9 days before initiating
inflammation demonstrated a proportional increase in the number of
cells lining the cavities. Two hours after carrageenan stimulation, the
synthesis of TNF-
and all chemokines but RANTES increased in
proportion to the lining cellularity, although no differences in
infiltrating leukocytes were found, suggesting that the early source of
these mediators is resident cells. To assess the contribution of
neutrophils to chemokine synthesis at later time points, we used
neutropenic animals. Neutrophil depletion caused a decrease in TNF-
(51%), KC (37%), MIP-1
(30%), and RANTES (57%) levels and a
2-fold increase in monocytes 4 h after challenge. No effect on
MIP-2 and MCP-1 levels was observed. The selective blockade of CXCR2 or
CCR1 inhibited neutrophil recruitment by 74% and 54%, respectively,
without a significant inhibition of monocytes. A differential effect on
TNF-
and MCP-1 levels was observed after these treatments,
indicating that the two receptors did not subserve a mere redundant
chemotactic role. Overall, our results suggest that chemokines
synthesized by resident cells play an important role in the evolution
of the inflammatory response.
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