Understanding Autoimmune Lung Involvement
Investigators at Cedars-Sinai have uncovered important insights into the pathophysiology of diffuse alveolar hemorrhage (DAH), a rare but dangerous complication that can occur in people with autoimmune diseases, such as vasculitis or systemic lupus erythematosus (SLE).
They also found the lung tissue samples showed increased expression of genes associated with harmful inflammation in the body. Specifically, they observed increased expression of genes involved in a phenomenon called endoplasmic reticulum stress. Normally proteins are folded in an area found in cells called the endoplasmic reticulum (ER). But when cells are stressed, unfolded proteins accumulate in the ER. This activates an ER stress response, which then tries to restore normal function to the ER. If the stress to the cells is too severe, ER stress can drive cell death.
But neutrophils and NETs, the investigators discovered, may drive ER stress in the epithelial cells lining the lung. By deleting an enzyme in neutrophils that is required for the release of NETs, the investigators reduced ER stress and prevented DAH in the lung.
"Our findings suggest that the activated neutrophils in the lung may cause the development of DAH by driving ER stress," Jefferies said.
The investigators also looked at samples of human lung epithelial cells, or the cells that line the lungs. When these samples were cultured with neutrophils from people with SLE, they showed more ER stress than when they were cultured with neutrophils from healthy people.
The findings shed light on what is driving autoimmune lung involvement and may contribute to the development of new drugs to treat DAH and autoimmune lung inflammation.
"Drugs that inhibit neutrophils and the release of NETs may reduce ER stress and lung damage," Jefferies said.