Published ahead of print on December 18, 2003, doi:10.1164/rccm.200302-224OC Am. J. Respir. Crit. Care Med., Volume 169, Number 6, March 2004, 687-695 A more recent version of this article appeared on March 15, 2004
Submitted on March 3, 2003 Enhanced pulmonary and systemic response to endotoxin in transgenic sickle miceJ. David Holtzclaw1,1 Pediatrics, Division of Hematology/Oncology and Bone Marrow Transplantation, Emory University School of Medicine, Atlanta, GA, USA, 2 Medicine, Atlanta Veterans Affairs Medical Center, Morehouse School of Medicine, Atlanta, GA, USA, 3 Hematology/Oncology, Emory University School of Medicine, Winship Cancer Institute, Atlanta, GA, USA, 4 Pulmonary, Allergy and Critical Care Medicine, Emory University School of Medicine, Atlanta, GA, USA * To whom correspondence should be addressed. E-mail: lewis_hsu{at}oz.ped.emory.edu.
Some suggest that sickle Cell Disease (SCD) is associated with a "proinflammatory state" that predisposes patients to acute chest syndrome in the setting of triggering factors. Conflicting data emerged when inflammation markers in SCD were compared to healthy individuals. Therefore, we examined transgenic sickle and control mice at baseline and with endotoxin (LPS) intraperitoneal injection to determine whether a proinflammatory state truly exists. At baseline, sickle mice had elevated levels of circulating leukocytes and sVCAM-1. No other differences were observed at baseline or in response to saline. However, LPS challenge was associated with significant increases in mortality (P<0.05), airway tone (P<0.03), serum and BAL levels of cytokines TNF Key words: Inflammation, Cytokines, adhesion molecules, plethysmography, cDNA microarray
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(P<0.03), IL-1
(P<0.02), and sVCAM-1 (P<0.01) in Sickle mice compared to controls. Furthermore, 4 hours after LPS, microarray analysis identified 413 genes differentially expressed in the Sickle mice (n=5) compared to only 7 in the controls (n=5). No difference in lung parenchyma was observed by light microscopy. This enhanced response to LPS suggests that sickle RBC confer a subclinical "proinflammatory state". This enhanced response to inflammatory insult, particularly by adhesion molecules such as sVCAM-1, could play a role in the increased susceptibility to pulmonary dysfunction that has been observed clinically in SCD.
