Children’s/Pitt Study Uncovers New Mechanism Governing the Integrity of Capillaries

Children’s Hospital of Pittsburgh of UPMC and University of Pittsburgh School of Medicine researchers have uncovered a new mechanism governing the integrity of capillaries, the smallest branches of the circulatory system. The study is published in the current issue of the journal Cell Reports.

Capillaries are lined by endothelial cells, which can maintain a water-tight barrier to prevent leakage of fluid from the bloodstream into surrounding tissue. However, under certain conditions, these cells can be stimulated to induce a rapid but temporary increase in the leakiness of this barrier. This allows fluid and immune cells to exit the bloodstream and accumulate in tissue leading to a condition known as “edema,” a cornerstone of the body’s inflammatory response.

While this acute increase in permeability is important for normal inflammation, it can cause more harm than good if left unchecked. In a broad range of conditions, from acute hypersensitivity responses such as a bee sting reaction or asthma attack, to brain swelling in trauma patients, excessive capillary leakiness can become life threatening.

A lack of knowledge about how endothelial cells regulate permeability has resulted in current therapies being mostly supportive in nature, directed at overcoming the consequences of edema and inflammation. This study highlights the unexpected role for an enzyme, MALT1, in mediating endothelial permeability initiated by several key inflammatory stimuli.

To study the role of MALT1, researchers used a mouse model which mimicked a state of septic shock, a life-threatening inflammatory condition which can lead to excessive fluid accumulation in the lungs. Mice genetically deficient in MALT1 enzymatic activity were protected from this fluid accumulation, demonstrating the crucial role of MALT1 activation in increasing leakiness of the endothelial barrier.

“Armed with this new knowledge, we can now begin to think about how targeting MALT1 might be an effective strategy for curtailing excessive, acute capillary leakiness in a range of clinical scenarios”, said Linda McAllister-Lucas, M.D., Ph.D., chief, Division of Pediatric Hematology/Oncology at Children’s Hospital and a senior author on the study.

To that end, the research group is now focused on compounds that were used several decades ago in the field of psychiatry but only recently discovered to inhibit MALT1 effectively.

“It’s particularly exciting to contemplate how an old class of pharmaceuticals, the phenothiazines, might be quickly repurposed for use in an entirely new therapeutic arena; the treatment of acute edema,” said

Peter Lucas, M.D., Ph.D., associate professor of pathology and pediatrics at Pitt School of Medicine and the study’s co-senior author.

The authors consider their current work as a “proof-of-principle” that pharmacologic MALT1 inhibition might have therapeutic benefit in conditions associated with capillary leak such as sepsis, trauma or allergic/hypersensitivity reactions.

The work was supported primarily by a grant from the National Heart, Lung, and Blood Institute of the National Institutes of Health (R01-HL082914).