ABSTRACT
A two-hit model of acid aspiration was used to examine the effect of keratinocyte growth factor (KGF) on chemokine levels and neutrophil recruitment into the lung. Mice were subjected to cecal ligation and puncture and then either KGF or saline, intratracheally (i.t.). Forty-eight hours later, the mice were given i.t. acid. After 8 h, neutrophil counts in bronchoalveolar lavage (BAL) fluid were significantly decreased in animals pretreated with KGF (23 +/- 4 x 10(3)/mouse) compared with saline (74 +/- 2 x 10(3)/mouse). In addition, the BAL fluid IL-6 levels were decreased in the KGF-treated group (88+/- 44 pg/mL) compared with the saline group (166 +/- 34 pg/mL). To examine the mechanism behind the KGF-induced reduction in neutrophil influx, the murine chemokines KC and macrophage inflammatory protein (MIP)-2alpha were measured. KC levels in plasma and BAL fluid were not significantly different between the treatment groups. Likewise, levels of MIP-2alpha in plasma were not affected by KGF treatment. However, 8 h after acid aspiration, MIP-2alpha concentrations were significantly lower in the KGF-treated group. The ratio of MIP-2alpha in BAL fluid versus plasma was lower in the KGF group (0.72 +/- 0.28) than in the saline group at 3 h (2.23 +/- 0.93) and also significantly lower in the KGF group (3.02 +/- 0.78) compared with the saline group (6.23 +/- 1.19) at 8 h. In this study, KGF pretreatment after acid aspiration was associated with reduced neutrophil recruitment into the lung and a decrease in MIP-2alpha gradients between BAL fluid and plasma.
Subject(s)
Fibroblast Growth Factors/administration & dosage , Fibroblast Growth Factors/pharmacology , Monokines/metabolism , Neutrophil Infiltration/drug effects , Neutrophils/drug effects , Pneumonia, Aspiration/immunology , Animals , Blood Cell Count , Bronchoalveolar Lavage Fluid/cytology , Chemokine CXCL2 , Chemokines/analysis , Chemokines/blood , Disease Models, Animal , Female , Fibroblast Growth Factor 7 , Lung/drug effects , Lung/immunology , Lung/pathology , Mice , Mice, Inbred BALB C , Neutrophils/immunology , Pneumonia, Aspiration/blood , Pneumonia, Aspiration/drug therapy , Pneumonia, Aspiration/pathologyABSTRACT
The secretion of calcitonin gene-related peptide (CGRP) and the chemokines KC and MIP-2 are increased in the animal models of endotoxemic and septic shock. We tested whether CGRP could modulate KC and MIP-2 secretion from different sources of macrophages after murine sepsis induced by cecal ligation and puncture (CLP). Macrophages were obtained from the peritoneal exudate and lung of female BALB/c mice 16 h after CLP and plated in culture with CGRP and/or LPS for 12 h. The results showed that peritoneal macrophage production of the chemokines (KC, MIP-2) and cytokines (TNF-alpha, IL-6) was markedly decreased in CLP mice. Alveolar macrophages did not display decreased cytokine/chemokines production after CLP. CGRP (0.1 nM-10 nM) partially reversed this decreased production of LPS-induced KC and MIP-2 from peritoneal macrophages. These results suggest that CGRP might be intimately involved in recruitment of neutrophils by promoting local production of the chemokines KC and MIP-2 in murine sepsis.
