From the Journals

Coagulation pathway may play role in IBD


 

FROM SCIENCE TRANSLATIONAL MEDICINE

A gene involved in coagulation may play a key role in inflammatory bowel disease (IBD) and offer a potential new treatment target, new research suggests.

Writing in Science Translational Medicine, researchers presented the findings of a transcriptome analysis of 1,800 intestinal biopsies from individuals with IBD across 14 different cohorts.

Their analysis revealed that the coagulation gene pathway is altered in a number of patients with active IBD and, in particular, among patients whose disease does not respond to anti–tumor necrosis factor (anti-TNF) therapy.

“Clinical studies have established that patients with IBD are at substantially increased risk for thrombotic events and those with active disease have abnormal blood coagulation parameters, but the function and mechanism remain unclear,” wrote Gerard E. Kaiko, PhD, from the University of Newcastle, Australia, in Callaghan and coauthors.

The analysis highlighted a particular component of the coagulation pathway – SERPINE1, which codes for the protein plasminogen activator inhibitor–1 (PAI-1) – whose expression was increased in colon biopsies taken from actively inflamed areas of disease, compared with biopsies of uninflamed areas, biopsies from patients in remission, or in biopsies from individuals without IBD.

The increased expression of SERPINE1/PAI-1 was mostly within epithelial cells, which the authors said supported the hypothesis that the gene is a key player in the inflammation/epithelium interface in the disease.

Researchers also found that SERPINE1 expression correlated with disease severity, and it was consistently higher in patients who had failed to respond to anti-TNF therapy. They suggested that SERPINE1/PAI-1 activity could potentially address an unmet clinical need for objective measures of disease activity and function as a way to predict response to biologic therapy.

“Although biologic therapies with anti-TNF are now a mainstay for IBD therapy, up to 40% of patients are nonresponsive, and patients lose responsiveness over time,” they wrote. “Furthermore, because more therapeutic options become available in IBD, a predictive biomarker is needed for personalized treatment.”

The authors further explored the role of SERPINE1/PAI-1 in an experimental mouse model of IBD. They found that colonic expression of the gene was around sixfold higher in mice with chemically induced colonic injury and inflammation, compared with untreated controls.

Researchers noted that PAI-1’s function is to bind and inhibit the activity of tissue plasminogen activator, which is a protein involved in the breakdown of blood clots and is coded by the gene PLAT.

They screened for which cytokine pathways might regulate PAI-1, PLAT, and tissue plasminogen activator, and they found that, while none increased SERPINE1 expression, interleukin-17A did appear to increase the expression of PLAT, which raises the possibility that IL-17A could counteract the effects of PAI-1.

The study also found that, in the colon biopsies from individuals with active disease, there was an imbalance in the ratio of PAI-1 to tissue plasminogen activator such that these biopsies showed lower levels of active tissue plasminogen activator.

“Therefore, the potentially protective mechanism of elevation of tPA [tissue plasminogen activator] does not occur properly in patients with IBD,” they wrote.

The next step was to see whether inhibiting the activity of SERPINE1 had any effect. In a mouse model of chemically induced colitis, the authors saw that treatment with a SERPINE1 inhibitor was associated with reduced weight change, mucosal damage, and reduced signs of inflammation, compared with untreated mice.

The study was supported by the Crohn’s & Colitis Foundation. Three authors were supported by grants from the National Health & Medical Research Council, one by the Cancer Institute NSW, one by an Alpha Omega Alpha – Carolyn L. Kuckein Student Research Fellowship, and two by the National Institutes of Health. Four authors have a patent pending related to PAI-1. Two authors declared advisory board positions with pharmaceutical companies, including the manufacturer of a product used in the study. Three authors are employees of Janssen R&D.

SOURCE: Kaiko GE et al. Sci. Transl. Med. 2019. doi: 10.1126/scitranslmed.aat0852.

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