Enhanced pulmonary and systemic response to endotoxin in transgenic sickle mice

JD Holtzclaw, D Jack, SM Aguayo… - American journal of …, 2004 - atsjournals.org
JD Holtzclaw, D Jack, SM Aguayo, JR Eckman, J Roman, LL Hsu
American journal of respiratory and critical care medicine, 2004atsjournals.org
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 with 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 soluble vascular cell …
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 with 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 soluble vascular cell adhesion molecule 1 (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 bronchoalveolar lavage levels of cytokines tumor necrosis factor-α (p < 0.03), interleukin-1β (p < 0.02), and sVCAM-1 (p < 0.01) in sickle mice compared with control subjects. Furthermore, 4 hours after LPS, microarray analysis identified 413 genes differentially expressed in the sickle mice (n = 5) compared with only 7 in the control subjects (n = 5). No difference in lung parenchyma was observed by light microscopy. This enhanced response to LPS suggests that the sickle red blood cell confers 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.
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