Michael L. Steer

Tufts Medical Center, Boston, Massachusetts, United States

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Publications (200)1689.91 Total impact

  • No preview · Article · Mar 2013 · Pancreatology
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    ABSTRACT: Pancreatic acinar cells express proteinase-activated receptor-2 (PAR2) that is activated by trypsin-like serine proteases and has been shown to exert model-specific effects on the severity of experimental pancreatitis - i.e. PAR2(-/-) mice are protected from experimental acute biliary pancreatitis but develop more severe secretagogue-induced pancreatitis. P2pal-18S is a novel pepducin lipopeptide that targets and inhibits PAR2. In studies monitoring PAR2-stimulated [Ca(2+)](i) changes, we show that P2pal-18S is a full PAR2 inhibitor in acinar cells. Our in vivo studies show that P2pal-18S significantly reduces the severity of experimental biliary pancreatitis induced by retrograde intraductal bile acid infusion which mimics injury induced by endoscopic retrograde cholangio-pancreatography (ERCP). This reduction in pancreatitis severity is observed when the pepducin is given before or 2 hours after bile acid infusion but not when it is given 5 hours after bile acid infusion. Conversely, P2pal-18S increases the severity of secretagogue-induced pancreatitis. In-vitro studies indicate that P2pal-18S protects acinar cells against bile acid-induced injury/death but it does not alter bile acid-induced intracellular zymogen activation. These studies are the first to report the effects of an effective PAR2 pharmacological inhibitor on pancreatic acinar cells and on the severity of experimental pancreatitis. They raise the possibility that a pepducin such as P2pal-18S might prove useful in the clinical management of patients at risk for developing severe biliary pancreatitis such as occurs following ERCP.
    Preview · Article · Dec 2012 · AJP Gastrointestinal and Liver Physiology
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    Full-text · Article · Aug 2012 · Bulletin of the American College of Surgeons
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    ABSTRACT: The roles of monocytes/macrophages and their mechanisms of action in the regulation of pancreatitis are poorly understood. To address these issues, we have employed genetically altered mouse strains that either express the human diphtheria toxin receptor (DTR) coupled to the CD11b promoter or have global deletion of TNF-α. Targeted, conditional depletion of monocytes/macrophages was achieved by administration of diphtheria toxin (DT) to CD11b-DTR mice. We show that in the absence of DT administration, pancreatitis is associated with an increase in pancreatic content of Ly-6C(hi) monocytes/macrophages but that this response is prevented by prior administration of DT to CD11b-DTR mice. DT administration also reduces pancreatic edema and acinar cell injury/necrosis in two dissimilar experimental models of acute pancreatitis (a secretagogue-induced model and a model elicited by retrograde pancreatic duct infusion of sodium taurocholate). In the secretagogue-elicited model, the DT-induced decrease in pancreatitis severity is reversed by adoptive transfer of purified Ly-6C(hi) monocytes harvested from non-DT-treated CD11b-DTR mice or by the transfer of purified Ly-6C(hi) monocytes harvested from TNF-α(+/+) donor mice, but it is not reversed by the transfer of Ly-6C(hi) monocytes harvested from TNF-α(-/-) donors. Our studies indicate that the Ly-6C(hi) monocyte subset regulates the severity of pancreatitis by promoting pancreatic edema and acinar cell injury/necrosis and that this phenomenon is dependent upon the expression of TNF-α by those cells. They suggest that therapies targeting Ly-6C(hi) monocytes and/or TNF-α expression by Ly-6C(hi) monocytes might prove beneficial in the prevention or treatment of acute pancreatitis.
    No preview · Article · Feb 2011 · Journal of Biological Chemistry
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    Full-text · Article · Feb 2010 · New England Journal of Medicine
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    ABSTRACT: Mechanistic studies of acute pancreatitis require animal models because clinical material is generally not available during the early phases of the disease. Here we describe a protocol to induce biliary pancreatitis by retrogradely infusing bile acids into the pancreatic duct of anesthetized mice. The resulting model replicates events believed to be responsible for the onset of clinical biliary (i.e., gallstone) pancreatitis and creates highly reproducible pancreatitis with a severity that depends on the concentration of infused bile acid. Pancreatitis reaches its maximal level of severity within 24 h of induction, and it resolves over the subsequent week. This protocol enables the investigator to use genetically modified strains of mice, and it requires only relatively simple and easily learned techniques of small animal surgery. With practice and gentle technique, the surgery (from induction of anesthesia to completion of the infusion) can be completed within 25 min per animal.
    No preview · Article · Feb 2010 · Nature Protocol
  • Michael L. Steer

    No preview · Article · Nov 2009 · Gastroenterology
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    ABSTRACT: The mechanisms by which reflux of bile acids into the pancreas induces pancreatitis are unknown. We reasoned that key events responsible for this phenomenon might be mediated by Gpbar1, a recently identified and widely expressed G-protein-coupled, cell surface bile acid receptor. Acute pancreatitis was induced in wild-type and Gpbar1(-/-) mice by either retrograde ductal infusion of taurolithocholic acid-3-sulfate (TLCS) or supramaximal secretagogue stimulation with caerulein. In vitro experiments were performed in which acini obtained from wild-type and Gpbar1(-/-) mice were exposed to either submicellar concentrations of TLCS (200-500 microM) or a supramaximally stimulating concentration of caerulein (10 nM). Gpbar1 is expressed at the apical pole of acinar cells and its genetic deletion is associated with reduced hyperamylasemia, edema, inflammation, and acinar cell injury in TLCS-induced, but not caerulein-induced, pancreatitis. In vitro, genetic deletion of Gpbar1 is associated with markedly reduced generation of pathological calcium transients, intracellular activation of digestive zymogens, and cell injury when these responses are induced by exposure to TLCS, but not when they are induced by exposure to caerulein. Gpbar1 may play a critical role in the evolution of bile-acid-induced pancreatitis by coupling exposure to bile acids with generation of pathological intracellular calcium transients, intra-acinar cell zymogen activation, and acinar cell injury. Acute biliary pancreatitis may be a "receptor-mediated" disease and interventions that interfere with Gpbar1 function might prove beneficial in the treatment and/or prevention of biliary acute pancreatitis.
    Preview · Article · Nov 2009 · Gastroenterology

  • No preview · Article · Nov 2008 · Pancreas

  • No preview · Article · Nov 2008 · Pancreas
  • J. Laukkarinen · G. Perides · M. Steer

    No preview · Article · Nov 2008 · Pancreas
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    ABSTRACT: Protease-activated receptor-2 (PAR2) is a 7-transmembrane G-protein-coupled tethered ligand receptor that is expressed by pancreatic acinar and ductal cells. It can be physiologically activated by trypsin. Previously reported studies (Namkung, W., Han, W., Luo, X., Muallem, S., Cho, K. H., Kim, K. H., and Lee, M. G. (2004) Gastroenterology 126, 1844-1859; Sharma, A., Tao, X., Gopal, A., Ligon, B., Andrade-Gordon, P., Steer, M. L., and Perides, G. (2005) Am. J. Physiol. 288, G388-G395) have shown that PAR2 activation exerts a protective effect on the experimental model of pancreatitis induced by supramaximal secretagogue (caerulein) stimulation. We now show that PAR2 exerts a worsening effect on a different model of experimental pancreatitis, i.e. one induced by retrograde pancreatic ductal infusion of bile salts. In vitro studies using freshly prepared pancreatic acini show that genetic deletion of PAR2 reduces bile salt-induced pathological calcium transients, acinar cell injury, and activation of c-Jun N-terminal kinase, whereas genetic deletion of PAR2 has the opposite or no effect on these pancreatitis-related events when they are elicited, in vitro, by caerulein stimulation. Studies employing a combination of trypsin inhibition and activation of PAR2 with the activating peptide SLIGRL show that all these differences indeed depend on the activation of PAR2. These studies are the first to report that a single perturbation can have model-specific and opposite effects on pancreatitis, and they underscore the importance of performing mechanistic pancreatitis studies using two dissimilar models of the disease to detect idiosyncratic, model-specific events. We suggest PAR2 activation exerts a worsening effect on the severity of clinical pancreatitis and that interventions interfering with PAR2 activation may be of benefit in the treatment of patients with severe pancreatitis.
    No preview · Article · Aug 2008 · Journal of Biological Chemistry
  • Jean-Louis Frossard · Michael L Steer · Catherine M Pastor

    No preview · Article · Mar 2008 · The Lancet
  • Jean-Louis Frossard · Michael L Steer · Catherine M Pastor
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    ABSTRACT: Acute pancreatitis is an inflammatory disease of the pancreas. Acute abdominal pain is the most common symptom, and increased concentrations of serum amylase and lipase confirm the diagnosis. Pancreatic injury is mild in 80% of patients, who recover without complications. The remaining patients have a severe disease with local and systemic complications. Gallstone migration into the common bile duct and alcohol abuse are the most frequent causes of pancreatitis in adults. About 15-25% of pancreatitis episodes are of unknown origin. Treatment of mild disease is supportive, but severe episodes need management by a multidisciplinary team including gastroenterologists, interventional radiologists, intensivists, and surgeons. Improved understanding of pathophysiology and better assessments of disease severity should ameliorate the management and outcome of this complex disease.
    No preview · Article · Feb 2008 · The Lancet
  • M.L. Steer · G. Perides
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    ABSTRACT: Conventionally, the distinction between acute and chronic pancreatitis is based on the issue of reversibility, in other words, can the functional and morphological pancreatic changes associated with the disease be completely reversed if the inciting cause(s) are removed and if no further attacks occur? This characteristic of so-called "acute pancreatitis" appears to be critical to its natural history and, at the extremes of its spectrum, it appears to distinguish acute pancreatitis from chronic pancreatitis, both in terms of its various inciting causes (i.e., its pathogenesis) and in terms of the cellular events that mediate its evolution (i.e., its pathophysiology). At the center of the spectrum, however, that distinction may break down and it must be recognized that there may exist considerable overlap, in terms of both pathogenesis and pathophysiology, between acute and chronic pancreatitis. This chapter will summarize current concepts regarding both the pathogenesis and the pathophysiology of acute pancreatitis. Our knowledge regarding the former is based primarily on clinical observations, while that regarding the latter is almost entirely based on observations made using models of acute pancreatitis induced in experimental animals.
    No preview · Article · Jan 2008
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    ABSTRACT: Most mechanistic studies of pancreatitis in mice employ the secretagogue-induced model. The currently reported studies were designed to develop an alternative, and possibly more clinically relevant, mouse model of pancreatitis. Na-taurocholate (10-50 microl, 1-5%) in saline, or saline alone, was retrogradely infused into the mouse pancreatic duct. The animals were killed 6-24 hours later and the severity of pancreatitis in the pancreatic head and tail was examined by quantitating hyperamylasemia, pancreatic edema, acinar cell necrosis, and pancreatic inflammation. In addition, intrapancreatic activation of trypsinogen, generation of IL-6, intrapulmonary sequestration of neutrophils, and alterations in lung compliance were evaluated. The effects of Na-taurocholate on in-vitro acinar cell calcium transients, viability, and trypsinogen activation were examined. Little or no evidence of pancreatitis was observed in mice infused with saline alone or in the tail of pancreata removed from animals infused with Na-taurocholate. In the head of the pancreas, evidence of pancreatitis was observed 12-24 hours after infusion of 20-50 microl 2-5% Na-taurocholate and the earliest morphological changes involved terminal duct and acinar cells. Intrapancreatic trypsin activity was transiently elevated within 5 minutes of Na-taurocholate infusion and pancreatic IL-6 levels were elevated 24 hours later. Under in-vitro conditions, Na-taurocholate triggered pathological acinar cell calcium transients, cell death, and calcium-dependent trypsinogen activation. This clinically relevant model of acute biliary pancreatitis yields reproducible results and its severity can be easily manipulated. It is ideally suited for use in mechanistic studies employing genetically modified mouse strains.
    Full-text · Article · Dec 2007 · Gut

  • No preview · Article · Nov 2007 · Pancreas

  • No preview · Article · Nov 2007 · Pancreas
  • J. Laukkarinen · E. R. Weiss · G. Perides · M. L. Steer

    No preview · Article · Nov 2007 · Pancreas
  • Michael L. Steer · George Perides

    No preview · Chapter · Oct 2007

Publication Stats

8k Citations
1,689.91 Total Impact Points


  • 2007-2013
    • Tufts Medical Center
      • Department of Surgery
      Boston, Massachusetts, United States
  • 2012
    • Partners in Health
      Boston, Massachusetts, United States
  • 1993-2010
    • Harvard University
      Cambridge, Massachusetts, United States
    • Beverly Hospital, Boston MA
      BVY, Massachusetts, United States
  • 2009
    • University of Massachusetts Boston
      Boston, Massachusetts, United States
  • 2005-2009
    • Tufts University
      • Department of Surgery
      Бостон, Georgia, United States
    • Boston Medical Center
      Boston, Massachusetts, United States
  • 1979-2002
    • Beth Israel Deaconess Medical Center
      • • Department of Surgery
      • • Department of Radiology
      Boston, Massachusetts, United States
  • 1977-2001
    • Harvard Medical School
      • Department of Surgery
      Boston, Massachusetts, United States
  • 1995
    • Boston University
      Boston, Massachusetts, United States
    • Yale-New Haven Hospital
      • Department of Pathology
      New Haven, Connecticut, United States
  • 1987
    • University of Milan
      • Center of Cytopharmacology CNR
      Milano, Lombardy, Italy
  • 1985
    • Beth Israel Medical Center
      • Department of Surgery
      New York City, New York, United States
  • 1976-1983
    • Hebrew University of Jerusalem
      • Department of Biological Chemistry
      Yerushalayim, Jerusalem, Israel
  • 1973-1975
    • Weizmann Institute of Science
      • Department of Mathematics