Simvastatin Cuts Heparin-Binding Protein in Acute Lung Injury
Statins may have a beneficial role in ALI. We have recently shown that oral administration of 80 mg simvastatin to patients with ALI reduced pulmonary and systemic inflammation. Simvastatin improved systemic organ failure with a trend to improvement in respiratory dysfunction. Multi-organ dysfunction is caused, at least in part, by increased endothelial permeability and simvastatin has been shown to improve lung permeability in endotoxin-induced ALI in mice. As HBP derived from neutrophils disrupts endothelial integrity causing vascular leakage and organ failure, we aimed to investigate the levels of plasma HBP in patients with ALI and if simvastatin modified those levels. As neutrophils play a central part in the pathogenesis of ALI, we hypothesised that HBP concentrations in plasma would be increased in patients with ALI. We found that plasma HBP levels in patients with ALI were significantly increased compared to healthy individuals. Other investigators found elevated levels of plasma HBP in patients with severe sepsis and septic shock and HBP concentrations higher or equal to 15 ng/ml were found in 87% of critically ill patients with sepsis. Furthermore, when plasma HBP levels reached this threshold, there was a 4-fold increase of the mortality rate among patients with sepsis.
We next investigated whether plasma HBP level was associated with mortality. We found that plasma HBP levels at enrolment were not significantly different between patients with ALI surviving ICU admission or not. In contrast, other investigators found elevated HBP levels at admission in other diseases including sepsis, and this was associated with an increased mortality at 28 days. We also observed that HBP levels decreased significantly at day 7 versus day 0 in ICU survivors but not in ICU non-survivors. Based on these findings, we propose that normalization of plasma HBP level over the time, rather than the concentration of HBP at enrolment, is associated with recovery. It is plausible that strategies to decrease plasma HBP levels may reduce endothelial leak and may be a potential therapeutic strategy to further investigate.
Simvastatin reduces pulmonary and systemic inflammation in patients with ALI and in a human model of ALI induced by inhaled LPS. Therefore, we investigated whether simvastatin reduced plasma HBP levels in patients with ALI. We found that patients treated with simvastatin had a greater fold reduction in plasma HBP levels at day 7 versus day 0 than those who received placebo. This relation persisted when corrected for neutrophil count suggesting this is not simply a reflect of reduced peripheral neutrophil counts but reduced neutrophil activation.
The relatively small sample size used in this study limits the interpretation of the data. Although we found that decreased plasma HBP levels was associated with survival and simvastatin decreased plasma levels of HBP in patients with ALI, simvastatin did not improve ALI survival. It would be necessary to conduct a larger study in patients with ALI to confirm the association between the administration of simvastatin, reduced plasma levels of HBP, and survival which is ongoing.
Pro-inflammatory cytokines and chemokines, which characterise ALI, induce expression of β2 integrins (LFA-1 and Mac-1) on the membrane surface of neutrophils and switch these adhesion receptors from a low to a high affinity ligand binding conformation. This change in conformation allows the β2 integrins to bind endothelial ligands, which is a prerequisite for extravasation and activation of neutrophil inflammatory functions including degranulation (and release of HBP). Interestingly, statins have been shown to bind to an allosteric site within the β2 integrin LFA-1 which prevents LFA-1 interacting with endothelial ligands. This has been shown to impair migration of neutrophils in a murine peritonitis model. Although statins do not bind Mac-1, the dominant β2 integrin expressed in neutrophils, simvastatin has been shown to reduce expression of Mac-1 on the membrane surface of circulating neutrophils by reducing the level of pulmonary CXC chemokines. Accordingly, potential mechanism for our finding is that simvastatin blocks β2 integrin-dependent release of HBP and other granule proteins.
Discussion
Statins may have a beneficial role in ALI. We have recently shown that oral administration of 80 mg simvastatin to patients with ALI reduced pulmonary and systemic inflammation. Simvastatin improved systemic organ failure with a trend to improvement in respiratory dysfunction. Multi-organ dysfunction is caused, at least in part, by increased endothelial permeability and simvastatin has been shown to improve lung permeability in endotoxin-induced ALI in mice. As HBP derived from neutrophils disrupts endothelial integrity causing vascular leakage and organ failure, we aimed to investigate the levels of plasma HBP in patients with ALI and if simvastatin modified those levels. As neutrophils play a central part in the pathogenesis of ALI, we hypothesised that HBP concentrations in plasma would be increased in patients with ALI. We found that plasma HBP levels in patients with ALI were significantly increased compared to healthy individuals. Other investigators found elevated levels of plasma HBP in patients with severe sepsis and septic shock and HBP concentrations higher or equal to 15 ng/ml were found in 87% of critically ill patients with sepsis. Furthermore, when plasma HBP levels reached this threshold, there was a 4-fold increase of the mortality rate among patients with sepsis.
We next investigated whether plasma HBP level was associated with mortality. We found that plasma HBP levels at enrolment were not significantly different between patients with ALI surviving ICU admission or not. In contrast, other investigators found elevated HBP levels at admission in other diseases including sepsis, and this was associated with an increased mortality at 28 days. We also observed that HBP levels decreased significantly at day 7 versus day 0 in ICU survivors but not in ICU non-survivors. Based on these findings, we propose that normalization of plasma HBP level over the time, rather than the concentration of HBP at enrolment, is associated with recovery. It is plausible that strategies to decrease plasma HBP levels may reduce endothelial leak and may be a potential therapeutic strategy to further investigate.
Simvastatin reduces pulmonary and systemic inflammation in patients with ALI and in a human model of ALI induced by inhaled LPS. Therefore, we investigated whether simvastatin reduced plasma HBP levels in patients with ALI. We found that patients treated with simvastatin had a greater fold reduction in plasma HBP levels at day 7 versus day 0 than those who received placebo. This relation persisted when corrected for neutrophil count suggesting this is not simply a reflect of reduced peripheral neutrophil counts but reduced neutrophil activation.
The relatively small sample size used in this study limits the interpretation of the data. Although we found that decreased plasma HBP levels was associated with survival and simvastatin decreased plasma levels of HBP in patients with ALI, simvastatin did not improve ALI survival. It would be necessary to conduct a larger study in patients with ALI to confirm the association between the administration of simvastatin, reduced plasma levels of HBP, and survival which is ongoing.
Pro-inflammatory cytokines and chemokines, which characterise ALI, induce expression of β2 integrins (LFA-1 and Mac-1) on the membrane surface of neutrophils and switch these adhesion receptors from a low to a high affinity ligand binding conformation. This change in conformation allows the β2 integrins to bind endothelial ligands, which is a prerequisite for extravasation and activation of neutrophil inflammatory functions including degranulation (and release of HBP). Interestingly, statins have been shown to bind to an allosteric site within the β2 integrin LFA-1 which prevents LFA-1 interacting with endothelial ligands. This has been shown to impair migration of neutrophils in a murine peritonitis model. Although statins do not bind Mac-1, the dominant β2 integrin expressed in neutrophils, simvastatin has been shown to reduce expression of Mac-1 on the membrane surface of circulating neutrophils by reducing the level of pulmonary CXC chemokines. Accordingly, potential mechanism for our finding is that simvastatin blocks β2 integrin-dependent release of HBP and other granule proteins.
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