Abstract
Chemokines activate and recruit specific leukocyte subpopulations. We sought to determine whether neutrophil migration, which can contribute to the development of ischemia-reperfusion injury, correlates with lung allograft rejection. Orthotopic left lung allotransplantation was performed from Brown Norway (donor) to Fisher 344 (recipient) rats. Because the role of activated neutrophils in the development of allograft rejection is believed to be biphasic, we used specific CXC receptor inhibition with antileukinate in 2 dosing regimens. Recipients were allocated into 4 groups; A (early administration) received 2 doses of anti-leukinate (10.0 mg/kg) intramuscularly 24 h before and immediately after transplantation; B (continuous administration) continuously received antileukinate intraperitoneally (10.0 mg/kg/day) for 7 days after surgery. Groups A or B were compared with individual controls that received PBS alone. The progression of rejection was assessed radiographically. Histologic evaluation of allograft rejection based on pathologic rejection grade, performed on day 7, demonstrated significantly lower histologic rejection in group B compared with the control group (2.1 ± 1.0 vs. 3.3 ± 0.5; P= 0.018), whereas there was no significant difference in group A compared with the control group. There were no significant differences between the aeration scores of groups A or B compared with their control groups. Our data suggest that neutrophils may play a promoting role in the development of allograft rejection, and blockage of neutrophil migration may suppress acute lung allograft rejection.
Highlights
In the early 1980s, lung transplantation was rarely used, but in the last decade it has become a widely available therapeutic option
It is known to inhibit IL-8–induced neutrophil chemotaxis and enzyme release [12] and has been considered a potent neutrophil activation inhibitor with the capability to protect lung tissue from acute lung injury induced by drugs [13] or sepsis [14]. These findings suggest that antileukinate or its derivatives might prove useful in lung allograft reperfusion injury caused by activated neutrophils due to the unrestrained action of CXC-chemokines
There were no significant differences in total surgical time and graft ischemic time in the 4 groups (Table 1)
Summary
In the early 1980s, lung transplantation was rarely used, but in the last decade it has become a widely available therapeutic option. Once neutrophils are exposed to inflammatory signals, activated neutrophils produce cytokines and chemokines to induce Th1 polarization of antigen-specific T lymphocytes that influence the T-cell immune response [11] These observations suggest a linkage between neutrophils and the development of acute cellular rejection. It is known to inhibit IL-8–induced neutrophil chemotaxis and enzyme release [12] and has been considered a potent neutrophil activation inhibitor with the capability to protect lung tissue from acute lung injury induced by drugs [13] or sepsis [14] These findings suggest that antileukinate or its derivatives might prove useful in lung allograft reperfusion injury caused by activated neutrophils due to the unrestrained action of CXC-chemokines. This study was designed to investigate whether suppression of neutrophil activation by this novel chemokine receptor antagonist affects the development and severity of ischemia-reperfusion injury following acute lung allograft rejection
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