Sepsis is a potentially life-threatening condition that occurs when the body’s response to an infection damages its own tissues. When the infection-fighting processes turn on the body, they cause organs to function poorly and abnormally. If the original infection is not treated, it can trigger an inflammatory response that may result in leaking blood vessels and impaired blood flow. Now, researchers at the University of California, San Diego (UCSD), School of Medicine, report they are working to better understand how they might intervene to restore blood vessel integrity during sepsis, trauma, or other conditions.
Their new mouse study is published in the journal Science Signaling in a paper titled, “Heat shock protein 27 activity is linked to endothelial barrier recovery after proinflammatory GPCR-induced disruption.”
“Vascular inflammation causes endothelial barrier disruption and tissue edema,” the researchers wrote. “Several inflammatory mediators act through G protein–coupled receptors (GPCRs), including protease-activated receptor-1 (PAR1), to elicit inflammatory responses. The activation of PAR1 by its ligand thrombin stimulates proinflammatory, p38 mitogen-activated protein kinase (MAPK) signaling that promotes endothelial barrier disruption. Through mass spectrometry phosphoproteomics, we identified heat shock protein 27 (HSP27), which exists as a large oligomer that binds to actin, as a promising candidate for the p38-mediated regulation of barrier integrity.”
The researchers discovered that a protein called HSP27 plays a role in regulating blood vessel leakage. Cells add and remove chemical tags on HSP27 to help breakdown or buildup blood vessel barrier.
“This new information will help us home in on the root cause of leaky blood vessels, rather than taking a broad strokes approach that may have many off-target effects,” said senior author JoAnn Trejo, PhD, professor of pharmacology and assistant vice chancellor of the Office of Health Sciences Faculty Affairs at UCSD School of Medicine.
According to Trejo, HSP27 binds to proteins that help form the cell’s “skeleton.” She and colleagues suspect that’s why HSP27 can affect blood vessel permeability—by fortifying the skeleton of cells that maintain the barrier.
The researchers discovered that during inflammation, GPCRs tell kinases to add chemical tags to HSP27. The tags disturb HSP27’s structure in a way that distresses blood vessel barriers. When HSP27 reassembles, the barriers recover. The researchers validated their lab studies in mice, where they found that inhibiting HSP27 increases blood vessel leakage.
The researchers had to overcome the challenge in targeting GPCRs to treat a disease is the fact that most act as master regulators, influencing several different cell functions. Inhibiting one GPCR may have many unintended consequences. By placing their attention further downstream, Trejo’s team is hoping to enable the development of blood vessel barrier-stabilizing drugs that are more precise and have fewer negative side effects.
“It’s become apparent that you can develop different molecules that can bind to receptor and ‘bias’ them—make them signal in a very specific way to some pathways but not others,” Trejo said. “It’s what we call biased agonism, and it’s a huge advantage for drug development. It means we can develop not just an on/off switch, but a drug that can switch a receptor ‘off’ or eight different types of ‘on.’ We want to be able to tweak which pathways are on and not touch others.”
The researchers are working to better understand cell signaling pathways that help blood vessels build resistance to injury and inflammation. Their study provides new potential targets for the development of drugs that shore up blood vessel barriers and hope for intervening to restore blood vessel integrity during sepsis.