Differential Effects of Macrophage Inflammatory Chemokine-2 and Keratinocyte-Derived Chemokine on Hemorrhage-Induced Neutrophil Priming for Lung Inflammation: Assessment by Adoptive Cells Transfer in Mice

Abstract

Prior studies have shown that hemorrhage (Hem) can serve as a priming stimulus for acute lung injury (ALI) triggered by subsequent septic challenge (cecal ligation and puncture, CLP). Furthermore, we have reported that in vivo antibody neutralization of the chemokines, macrophage inflammatory chemokine-2 (MIP-2) and keratinocyte-derived chemokine (KC), immediately after Hem appears to differentially effect the onset of ALI. However, although we hypothesize that this is due to divergent effects of MIP-2 and KC on Hem-induced neutrophil (PMN) priming, this has not been tested. To examine this hypothesis, PMN donor mice were Sham-Hem or Hem for 90 min at 35 +/- 5 mmHg and were then administered anti-MIP- 2 (Hem/anti-MIP2), anti-KC (Hem/anti-KC), or nonspecific immunoglobulin (Ig) G (Hem/IgG) during resuscitation (Ringer's lactate = four times the amount of drawn blood volume). Twenty-four hours post-Hem, the peripheral blood PMN were purified from these donor animals and were introduced into PMN-depleted recipient mice [depleted by prior anti-Gr1 (mouse PMN-specific marker) antibody treatment]. One hour after PMN transfer, recipient mice were subjected to CLP, euthanized 24 h later, and plasma as well as lung tissue samples were collected. PMN influx was assessed by myeloperoxidase assay (MPO; microU/mg protein) and histologically (IL-6, MIP-2, KC, and IL-10 levels) by enzyme-linked immunoabsorbant assay (ELISA; ng/mg). The results show that donor PMN from Hem/IgG but not Sham-Hem mice produce increased PMN influx (increased MPO, increased % esterase+ cells in tissue) into the lung and local tissue inflammation (increased IL-6/MIP-2, decreased IL-10) in PMN-depleted CLP recipient mice, which was attenuated in mice receiving cells from Hem/anti-MIP-2 but not Hem/anti-KC treated donors. Interestingly, although Hem/anti-MIP-2 donor PMN produced comparable effects on blood IL-6/MIP-2 levels, they were ineffective in altering the change in plasma IL-10/KC levels induce by Hem. Taken together, these data demonstrate that Hem-induced priming of PMN not only mediates ALI in the mouse, but also that this process is differentially effected by MIP2 and KC, despite the fact that both signal through CXCR2.

The Chemokine Receptor CXCR2 Ligand KC (CXCL1) Mediates Neutrophil Recruitment and Is Critical for Development of Experimental Lyme Arthritis and Carditis

“…In addition, levels of LIX and MIP-2 in ankles and hearts were unaltered in the KC Ϫ/Ϫ tissues, demonstrating a lack of compensatory changes during KC deficiency. Our results are in agreement with other studies suggesting that, despite apparent functional redundancy in vitro, in vivo these chemokines are under differentially regulated control, as illustrated by distinct tissue expression profiles, and likely have unique biological functions (4,17,32,44). Although functional redundancy is likely to exist under certain conditions in vivo, neutrophil recruitment and subsequent disease development during murine Lyme borreliosis appear to be mediated primarily via the KC/CXCR2 axis.…”

Stimulation of Brain AMP-Activated Protein Kinase Attenuates Inflammation and Acute Lung Injury in Sepsis

“…Chemokines keratinocyte derivedchemokine (KC) and macrophage inflammatory protein-2 (MIP-2) both have been shown to participate in the pathogenesis of lung injury (36,37). The mRNA levels of KC and MIP-2 increased by 748-and 1415-fold, respectively, in the vehicle as compared with the sham (Figures 6A, B).…”

Mechanisms of Coagulation Abnormalities and Trauma

“…25,27 Protein C activation is further diminished by protease cleavage of thrombomodulin (TM) as well as by a direct transcriptional down regulation of TM by circulating TNF-and IL-6. 28 Protein C stores are also depleted by an 23 accelerated conversion to activated protein C (aPC), degradation by protein C inhibitor (PCI), and impaired hepatic biosynthesis, all of which contribute to a state of protein C and aPC depletion in sepsis. 25 Mesters has reported that the depletion of protein C (and reduction of activated protein C plasma levels) precedes the onset of any sepsis by an average of 12 hours.…”

“…For mortality analysis, patients surviving to hospital discharge were assumed to still be alive. Secondary outcome measures were also recorded for 28-day ventilator-free days, acute lung injury (American-European consensus conference definition) 21 , VAP and acute renal injury (Acute Dialysis Quality Initiative consensus conference definition) 23 and blood transfusions required in the first 24 hours. Depleters were defined as having a slope more negative than the median during both time periods.…”