From the AGA Journals

Inhibiting integrin-mediated activation might help treat, reverse chronic pancreatitis

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Proof of effect in ‘more robust’ models needed

Integrins are transmembrane proteins that organize epithelial cells and transmit signals from the tissue matrix. These proteins consist of two subunits that partner to form more than 20 specific combinations, are induced upon tissue injury, and act as signaling molecules that mediate inflammatory and wound-healing responses. The utility of targeting integrins has been established by drugs such as vedolizumab, which targets specific integrins to dampen injury in inflammatory bowel disease.

Dr. Chuhan Chung

Specific integrins also mediate profibrotic responses by activating TGF-beta, the major fibrogenic cytokine. An arginine-glycine-aspartic acid (RGD) integrin-binding motif found on the TGF-beta molecule triggers this activation upon interaction with specific integrins. Blocking the RGD-integrin interaction reduces fibrosis in multiple organs including the lung, liver, and kidney.

In the current issue of Cellular and Molecular Gastroenterology and Hepatology, Ulmasov et al. report on the use of a synthetic peptide (CWHM-12) in a model of chronic pancreatitis. This peptide mimetic antagonizes the RGD interaction with integrins, thereby limiting TGF-beta activation. Using a cerulein-induced pancreatic fibrosis model, the authors demonstrated that CWHM-12 inhibits pancreatic stellate cell (PSC) activation and generation of active TGF-beta. CWHM-12 suppressed fibrosis when administered prior to cerulein injection, and to a lesser extent, during the course of generating fibrosis. The alpha-v-beta1 integrin was identified as a critical integrin and was expressed at high levels in the murine pancreas, primary PSCs, and further in cerulein-induced pancreatitis.

Dr. Fred Gorelick

Limitations of the current study warrant comment. The most obvious is that this model does not generate true chronic pancreatitis, because unlike chronic pancreatitis, fibrosis resolves spontaneously. Proof of effect in more robust chronic pancreatitis models is needed. Off-target effects are also suggested by the finding that serum white blood counts were significantly higher with CWHM-12. Finally, the chronicity and unpredictability of human chronic pancreatitis make this preclinical study an early starting point for determining whether CWHM-12 has true “clinical legs.”

Dr. Chuhan Chung and Dr. Fred Gorelick are in the department of medicine, Yale University, New Haven, Conn., and the VA Connecticut Healthcare System, West Haven.


 

FROM CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY

Integrins that bind arginine-glycine-aspartic acid (RGD) activated stellate cells in the pancreas, inducing pancreatic fibrogenesis in mice, researchers reported in the July issue of Cellular and Molecular Gastroenterology and Hepatology.

“Small-molecule antagonists of this interaction might be developed for the treatment of pancreatic fibrotic diseases,” wrote Dr. Barbara Ulmasov and her associates at Saint Louis University.

Cytokine transforming growth factor beta, or TGFB, plays a “central” role in the activation of pancreatic stellate cells and the promotion of fibrogenesis, both in the pancreas and in other organs, the investigators noted. Because latent TGFB is “abundantly present” in the pancreas and most other tissues, it might be more important to control the activation of TGFB than its expression, they added. Studies of other organs have shown that TGFB is activated when integrins of the av family bind the RGD sequence, but no one had determined whether this was true for pancreatic fibrogenesis, Dr. Ulmasov and her associates asserted (Cell Mol Gastroenterol Hepatol. 2016 Mar 16. doi: 10.1016/j.jcmgh.2016.03.004).

Therefore, they repeatedly injected female C57BL/6 mice with cerulein to induce pancreatic fibrogenesis, and gave a group of control mice sterile saline instead. The mice then received continuous infusions of a small molecule called CWHM-12, which is an antagonist of RGD-integrin that is known to prevent both pulmonary and hepatic fibrosis in mice. After euthanizing the mice, the researchers measured pancreatic parenchymal atrophy, fibrosis, and activation of pancreatic stellate cells. They also studied TGFB activation in an established line of pancreatic stellate cells from rats.

Pancreatic stellate cells expressed messenger RNAs encoding RGD-binding integrins, the investigators found. The mice that received cerulein had higher levels of these integrins than the mice that received saline, and the cerulein group also had more disrupted acinar cell architecture, tubular complexes, and infiltrations of inflammatory cells. Mice that received prophylactic CWHM-12 had only somewhat less acinar cell loss and atrophy than the control mice, and had similar levels of inflammatory cell infiltration, but had “dramatically” lower levels of pancreatic fibrosis, the researchers said. Even if mice received CWHM-12 several days after starting cerulein, they still had less fibrosis and activation of TGFB than if they received saline, they noted.

The established line of pancreatic stellate cells “could robustly activate endogenously produced TGFB,” the investigators also reported. Furthermore, CWHM-12 “potently blocked TGFB activation,” unlike the control compound. Taken together, the findings illustrate the “critical role of RGD-binding integrins in chronic pancreatitis, and the promising potential to arrest or possibly even reverse pancreatic fibrosis using a pharmacologic approach to inhibiting integrin-mediated TGFB activation,” the researchers concluded.

The National Pancreas Foundation and the Frank R. Burton Memorial Fund supported the study. Dr. Ulmasov had no disclosures. Three coinvestigators reported being consultants and/or holding equity in Integrin Therapeutics, Nimbus Therapeutics, Bristol-Myers Squibb, Janssen, Mitsubishi Tanabe, Conatus, and Scholar Rock.

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