New perspectives for Sepsis Therapeutics

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Sepsis occurs when the body works so hard to fight an infection that the overactive immune system damages the patient’s own tissues as collateral damage. As a result, blood vessels can leak and major organs cannot get the oxygen and nutrients they need to sustain life. Sepsis is one of the main reasons patients, many of them with COVID-19, end up in the intensive care unit. The disease is notoriously difficult to treat, and no medication helps stabilize the cell barrier that lines blood vessels.

Researchers at the University of California San Diego School of Medicine are working to better understand how the body controls the permeability of blood vessels and how they might intervene to restore the integrity of blood vessels during sepsis, trauma or other conditions.

The team recently discovered that a protein called HSP27 plays a role in regulating blood vessel leakage. To help break down or build up the barrier of blood vessels, cells add and remove chemical labels on HSP27.

This image, taken by confocal microscopy, shows a blood vessel. The actin protein, which helps build the skeleton of a cell, is marked in green. Thrombin, a pro-inflammatory mediator, causes gaps between cells in the blood vessel barrier. When the immune system is overactivated, as happens in sepsis, blood vessels can leak and major organs cannot get the oxygen and nutrients they need to stay alive.

The study, published on August 31, 2021 in
Scientific signage, provides potential new targets for the development of drugs that strengthen blood vessel barriers, thereby preventing fluid loss.

“This new information will help us identify the root cause of blood vessel leaks, rather than taking a general approach that can have many off-target effects,” said lead author JoAnn Trejo, PhD, professor of pharmacology and Deputy Vice-Chancellor. from the Business Office of the Faculty of Health Sciences at UC San Diego School of Medicine.

The barriers of the blood vessels must be dynamic – sufficiently permeable for immune cells to escape to reach the site of an infection, for example, but not so permeable that the situation becomes life-threatening. According to Trejo, HSP27 binds to proteins that help form the “backbone” of the cell. She and her colleagues suspect that this is why HSP27 may affect the permeability of blood vessels – by strengthening the skeleton of the cells that maintain the barrier.

Trejo has a long history of studying G protein coupled receptors (GPCRs), proteins embedded in cell membranes throughout the body, where they act as signal transducers, allowing cells to respond to their external environment. GPCRs play a crucial role in most biological functions. About a third of all therapeutic drugs on the market work because they influence GPCR signals.

In their latest study, the team found that during inflammation, GPCRs tell enzymes called kinases to add chemical (phosphate) tags to HSP27. The tags disrupt the structure of HSP27 in a way that disrupts blood vessel barriers. When HSP27 reassembles, the barriers are reestablished. The researchers validated their lab studies in mice, where they found that inhibiting HSP27 increases blood vessel leakage.

A challenge in targeting GPCRs to treat disease is the fact that most act as primary regulators, influencing several different cellular functions. Inhibiting a GPCR can have many unintended consequences. By focusing further downstream – not targeting the master GPCR but individual targets on which it acts, such as HSP27 – the Trejo team hopes to enable the development of blood vessel barrier stabilizing drugs that are more precise and have fewer negative side effects.

“It has become evident that you can develop different molecules that can bind to the receptor and ‘skew’ them – get them to signal in a very specific way to some pathways but not others,” Trejo said. “This is what we call bias agonism, and it’s a huge benefit for drug development. This means that we can develop not only an on / off switch, but a drug that can turn off a receptor or eight different types of activation. We want to be able to change the ways and not touch the others. “

The team plans to explore other cell signaling pathways that help blood vessels build resistance to injury and inflammation.

Co-authors include: Cara C. Rada, Hilda Mejia-Pena, Isabel Canto Cordova, Joshua Olson, Jacob M. Wozniak, David J. Gonzalez, Victor Nizet, UC San Diego; and Neil J. Grimsey, University of Georgia.

Funding for this research came, in part, from the National Institutes of Health (grants R35GM127121, TRDRP27DT-0009, T32GM007752).


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