Complement slows heart cells
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《实验药学杂志》
The complement activation product C5a prevents heart cells from contracting, according to Niederbichler and colleagues on page 53. This finding may help explain the cardiac dysfunction commonly seen in patients with septic shock—a disease caused by bacterial infections that is characterized in part by the robust activation of the complement system.
A central component of septic shock is decreased heart function, which deprives tissues of oxygen and nutrients and can progress to fatal multiorgan failure. Past studies have shown that a "myocardial depressant factor" is released into the serum during sepsis, with most studies attributing the depressant activity to proinflammatory cytokines released by immune cells responding to the infection.
Robust activation of the complement cascade is another hallmark of bacterial sepsis. Complement is a series of plasma proteins that helps destroy infecting microbes and attracts immune cells to sites of infection. C5a activates immune cells, such as neutrophils, which can then attack and kill the invading bacteria. But too much C5a can be deleterious, as blocking the protein or its receptor increases survival in rodent models of septic shock. This group previously showed that excessive C5a somehow prevents the activation of MAP kinase signaling in neutrophils, which jams up downstream signals and robs the cells of their ability to destroy bacteria.
The receptor for C5a (C5aR) is also expressed on airway cells, including bronchial epithelial cells and smooth muscle cells, but a link between complement and sepsis-induced cardiac dysfunction had not been directly investigated. Niederbichler and colleagues now show that cardiomyocytes, which help control heartbeat, also express C5aR—possibly to increase blood flow in response to infection or stress.
But as with neutrophils, too much C5a was bad for cardiomyocytes. Treatment of cardiomyocytes with high concentrations of C5a impaired their ability to contract. Blocking the interaction between C5a and its receptor in rats relieved the sepsis-induced drop in blood pressure. The authors are now investigating the molecular pathways that link C5aR signaling to the contractile machinery of the cell; they suspect that excessive C5a might induce a signaling paralysis in cardiomyocytes similar to that seen in neutrophils.
A central component of septic shock is decreased heart function, which deprives tissues of oxygen and nutrients and can progress to fatal multiorgan failure. Past studies have shown that a "myocardial depressant factor" is released into the serum during sepsis, with most studies attributing the depressant activity to proinflammatory cytokines released by immune cells responding to the infection.
Robust activation of the complement cascade is another hallmark of bacterial sepsis. Complement is a series of plasma proteins that helps destroy infecting microbes and attracts immune cells to sites of infection. C5a activates immune cells, such as neutrophils, which can then attack and kill the invading bacteria. But too much C5a can be deleterious, as blocking the protein or its receptor increases survival in rodent models of septic shock. This group previously showed that excessive C5a somehow prevents the activation of MAP kinase signaling in neutrophils, which jams up downstream signals and robs the cells of their ability to destroy bacteria.
The receptor for C5a (C5aR) is also expressed on airway cells, including bronchial epithelial cells and smooth muscle cells, but a link between complement and sepsis-induced cardiac dysfunction had not been directly investigated. Niederbichler and colleagues now show that cardiomyocytes, which help control heartbeat, also express C5aR—possibly to increase blood flow in response to infection or stress.
But as with neutrophils, too much C5a was bad for cardiomyocytes. Treatment of cardiomyocytes with high concentrations of C5a impaired their ability to contract. Blocking the interaction between C5a and its receptor in rats relieved the sepsis-induced drop in blood pressure. The authors are now investigating the molecular pathways that link C5aR signaling to the contractile machinery of the cell; they suspect that excessive C5a might induce a signaling paralysis in cardiomyocytes similar to that seen in neutrophils.