Differential flux of macrophage inflammatory protein-2 and cytokine-induced neutrophil chemoattractant from the lung after intrapulmonary delivery

Abstract

Zamjahn JB, Quinton LJ, Mack JC, Frevert CW, Nelson S, Bagby GJ. Differential flux of macrophage inflammatory protein-2 and cytokine-induced neutrophil chemoattractant from the lung after intrapulmonary delivery. Am J Physiol Lung Cell Mol Physiol 301: L568 -L574, 2011. First published July 8, 2011 doi:10.1152/ajplung.00340.2010.-Previously we showed that cytokine-induced neutrophil chemoattractant (CINC), but not macrophage inflammatory protein-2 (MIP-2), is detected in plasma after intratracheal challenge with LPS or the particular chemokines. To further understand the differences between CINC and MIP-2 flux from the lung, we attempted to detect the two chemokines in isolated erythrocytes and leukocytes in rats after intratracheal LPS challenge. In response to intratracheal LPS, we found both CINC and MIP-2 in isolated erythrocytes and leukocytes, suggesting that MIP-2 produced in the LPS-challenged lung entered the circulation like CINC. To assess the relative flux of CINC and MIP-2 from the intra-alveolar compartment into the blood, experiments were performed in rats implanted with vascular catheters in which both chemokines were either injected intratracheally (5 g) or infused intravenously (20 ng/min) and subsequently measured in plasma or with the cellular elements. Both chemokines appeared in the blood following intratracheal injection, with CINC detected in plasma and cells but MIP-2 only detected in the cellular fraction of blood. Infusion of both chemokines allowed detection of MIP-2 and CINC in plasma and with the cellular elements, which allowed us to calculate clearance for each chemokine and to assess CINC and MIP-2 rates of appearance (Ra) following intratracheal injection. On the basis of plasma and whole blood clearance, CINC Ra was more than sevenfold and fourfold higher, respectively, than MIP-2 Ra. This analysis indicates that differences exist in the rate of flux of CINC and MIP-2 across the epithelial/endothelial barrier of the lung, despite similar molecular size.Duffy antigen receptor for chemokines; intratracheal chemokines; intratracheal LPS; chemokines CXC CHEMOKINES ARE A FAMILY of related polypeptide molecules that are potent immune cell chemotactic factors (9). Members bearing a NH 2 -terminal ELRϩ sequence upstream from the conserved cysteine residues are potent inducers of neutrophil chemotaxis (14, 29). Cytokine-induced neutrophil chemoattractant (CINC) and macrophage inflammatory protein-2 (MIP-2) are rat ELRϩ CXC chemokines (functional counterparts to human CXCL8/IL-8), which have been shown to increase in lungs challenged with bacteria and to be responsible for neutrophil migration into the alveoli (4,5,20,24). Antibody neutralization of either chemokine significantly attenuates neutrophil migration into the intrapulmonary compartment during infection and decreases bacterial clearance (5, 7, 28).Previously we reported that CINC, but not MIP-2, appears in the plasma in response to intratracheal (IT) challenge with LPS despite their similar molecular size (7.8 and 7.9 kDa, res...

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