Cells that die with a bang contribute to high death rate in bloodstream infections

When these blood vessel cells come into contact with bacterial toxins called lipopolysaccharides, an explosive form of cell death known as pyroptosis occurs. Pyroptosis is initiated by an enzyme called caspase-11 in mice, and caspases 4 and 5 in humans. Without these enzymes, pyroptosis cannot occur, making these caspases attractive targets for drugs that can prevent tissue damage caused by infections.

"There are multiple ways a cell can die," said Dr. Jalees Rehman, associate professor of medicine and pharmacology in the UIC College of Medicine and co-lead author on the paper published in the Journal of Clinical Investigation. "In pyroptosis, cells go out with a bang."

Pyroptosis has only been documented in a few cell types, most notably in immune cells called macrophages. In pyroptosis, an external trigger activates caspases inside the cell, which in turn activate pro-inflammatory molecules called cytokines. As the cell membrane breaks down, the cytokines burst from the cell and signal to nearby immune cells to flock to the area to neutralize germs and prevent further damage. The word 'pyroptosis' is derived from the Greek word for fire.

Pyroptosis likely evolved as a useful alarm signal to amplify the inflammatory response by releasing potent cytokines in the setting of an infection. While the burst of cytokines help signal to nearby immune cells that a strong response is needed, in some severe infections cytokines released by pyroptosis can cause excessive tissue injury.

During a severe infection, bacteria that release lipopolysaccharides can enter the bloodstream. These infections are especially dangerous if they get into the blood vessels of the lungs. When large numbers of cells lining the blood vessels in the lungs come into contact with the bacterial toxins, the blood vessels become leaky and allow fluid to enter the lungs. This severe complication of bloodstream infections is called acute lung injury. Gas exchange in the lungs is severely compromised during acute lung injury, which is one reason for the high death rates of affected patients.

"Our work shows that pyroptosis of endothelial cells that line blood vessels may be one of the reasons why bacterial infections can cause such severe injury to the lung in some patients," said Asrar Malik, Schweppe Family distinguished professor and head of pharmacology in the UIC College of Medicine and co-lead author on the paper.

Approximately 200,000 people in the U.S. experience acute lung injury each year, and up to 30 to 40 percent of all cases can be fatal. The current standard treatment is supportive care, such as artificial ventilation.

The researchers observed that mice injected with lipopolysaccharide or bacteria that release lipopolysaccharides had very high mortality rates except for mice where the gene for caspase 11 had been deleted in blood vessel endothelial cells. These mice had much higher survival rates and less fluid in their lungs.

"Caspase-11 is clearly required for the activation of pyroptosis in the endothelial cells of mice," Rehman said. "Drugs that block this pathway or the corresponding human caspases 4 and 5 could help prevent or reduce the extent of lung injury."

Kwong Tai Cheng, Shiqin Xiong, Zhiming Ye, Zhigang Hong, Anke Di, Kit Man Tsang, Xiaopei Gao, Shejuan An, Manish Mittal and Stephen Vogel, of UIC, and Edward Miao of the University of North Carolina, Chapel Hill, are co-authors on the paper.

This research was supported by National Institutes of Health grants R01-HL45638, P01-HL60678, P01-HL077806, T32-HL007829, R01-HL118068, R01-HL90152, R01-AI097518, R01-AI119073, and the Yang Biomedical Scholars Award.