May 5, 2020 / 3:51 PM / 2 months ago

Inhibiting JNK signaling, BNP in sepsis could stabilize blood pressure and boost survival

NEW YORK (Reuters Health) - Inhibition of c-Jun N-terminal kinase (JNK) or B-type natriuretic peptide (BNP) can curb septic hypotension, according to studies in mice.

“BNP, which the heart secretes in the blood when it is stressed, contributes in lowering blood pressure during sepsis,” said Dr. Konstantinos Drosatos of the Lewis Katz School of Medicine at Temple University, in Philadelphia. If blood pressure becomes uncontrolled, he told Reuters Health by email, “the patient enters the point of no return and develops septic shock that is lethal.”

In a paper in JCI insight, Dr. Drosatos and colleagues note that in previous work they found that JNK inhibition corrects cardiac dysfunction and suppresses cardiac BNP mRNA in endotoxemia.

In the current study, the team observed a direct relationship between JNK and BNP molecules. A c-Jun activating protein attaches to the gene that encodes BNP, switching it on and leading to the production of BNP. In sepsis, the BNP-encoding gene is always on leading to excess secretion of BNP.

Using mouse models, the team blocked either JNK activation, using a chemical inhibitor, or BNP activity, using an antibody that they had developed earlier. JNK inhibition yielded the most robust benefits, but inhibition of either molecule also led to improvements in survival in mice with induced sepsis.

“At a clinical level, JNK or BNP inhibition could stabilize blood pressure and give other medications, such as antibiotics, time to work,” Dr. Drosatos said in a statement. “This strategy could be used alongside current supportive strategies, which attempt to slow or prevent fluid loss to stabilize blood pressure.”

In fact, Dr. Drosatos told Reuters Health, “we have designed a study to use BNP measurements along with non-invasive echocardiography to identify high-risk sepsis patients and stratify them in more effective therapies.”

President of the Shock Society Dr. Marc Jeschke of Sunnybrook Health Science Centre, in Toronto, Canada, who was not involved in the research, told Reuters Health by email that this study is of particular relevance as it shows that “JNK is an important signalling molecule to affect blood pressure and responses to sepsis.”

SOURCE: JCI Insight, online April 23, 2020.

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