Cathepsin L Inactivates Human Trypsinogen, Whereas Cathepsin L-Deletion Reduces the Severity of Pancreatitis in Mice

Wartmann, Thomas; Mayerle, Julia; Kähne, Thilo; Sahin–Tóth, Miklós; Ruthenbürger, Manuel; Matthias, R.; Kruse, Anne; Reinheckel, Thomas; Peters, Christoph; Weiss, Frank Ulrich; Sendler, Matthias; Lippert, H.; Schulz, Hans–Ulrich; Aghdassi, Ali; Dummer, A.; Teller, Steffen; Halangk, Walter; Lerch, Markus M.

doi:10.1053/j.gastro.2009.10.048

Cited by 115 publications

(100 citation statements)

References 30 publications

(55 reference statements)

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“…To this end, we measured (51) the effects of starvation and pancreatitis on the processing and activities of two major lysosomal hydrolases, cathepsins (Cat) B and L. Both cathepsins are relevant for pancreatitis: CatB proteolytically converts trypsinogen to trypsin (32,75,79), whereas CatL degrades both trypsinogen and trypsin (51,88). We found that starvation has little effect on pancreatic activities of CatB and CatL and their processing into fully mature, active forms.…”

Section: Lysosomal Dysfunction and Impaired Autophagy In Pancreatitismentioning

confidence: 99%

“…7). Indeed, we (51) and the groups of Markus Lerch and Walter Hallangk (32,88) showed that these cathepsins have opposite roles in trypsin accumulation: whereas CatB converts trypsinogen to trypsin, CatL does not activate trypsinogen but, on the contrary, degrades both trypsin and trypsinogen. We propose (51) that in pancreatitis, because of defective lysosomal function, CatL activity is not sufficient to degrade activated proteases (such as trypsinogen), resulting in trypsin accumulation in autophagic 2706 GUKOVSKY ET AL.…”

Section: Lysosomal Dysfunction and Impaired Autophagy In Pancreatitismentioning

confidence: 99%

“…Another regulator of cell death responses of pancreatitis is p53; we have recently shown (57) that in CR pancreatitis, neutrophils infiltrating the pancreas suppress acinar cell apoptosis (and thus facilitate necrosis) through down-regulating p53/caspase-2 pathway. There is also some evidence that acinar cell death in pancreatitis is regulated by lysosomal pathways (7,32,75,88).…”

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Organellar Dysfunction in the Pathogenesis of Pancreatitis

Gukovsky

Pandol

Gukovskaya

2011

Antioxidants & Redox Signaling

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Significance: Acute pancreatitis is an inflammatory disease of exocrine pancreas that carries considerable morbidity and mortality; its pathophysiology remains poorly understood. During the past decade, new insights have been gained into signaling pathways and molecules that mediate the inflammatory response of pancreatitis and death of acinar cells (the main exocrine pancreas cell type). By contrast, much less is known about the acinar cell organellar damage in pancreatitis and how it contributes to the disease pathogenesis. Recent Advances: This review summarizes recent findings from our group, obtained on experimental in vivo and ex vivo models, which reveal disordering of key cellular organelles, namely, mitochondria, autophagosomes, and lysosomes, in pancreatitis. Our results indicate a critical role for mitochondrial permeabilization in determining the balance between apoptosis and necrosis in pancreatitis, and thus the disease severity. We further investigate how the mitochondrial dysfunction (and hence acinar cell death) is regulated by Ca 2+ , reactive oxygen species, and BclxL, in relation to specific properties of pancreatic mitochondria. Our results also reveal that autophagy, the principal cellular degradative, lysosome-driven pathway, is impaired in pancreatitis due to inefficient lysosomal function, and that impaired autophagy mediates two key pathological responses of pancreatitis-accumulation of vacuoles in acinar cells and the abnormal, intra-acinar activation of digestive enzymes such as trypsinogen. Critical Issues and Future Directions: The findings discussed in this review indicate critical roles for mitochondrial and autophagic/lysosomal dysfunctions in the pathogenesis of pancreatitis and delineate directions for detailed investigations into the molecular events that underlie acinar cell organellar damage. Antioxid. Redox Signal. 15, 2699-2710.

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Section: Lysosomal Dysfunction and Impaired Autophagy In Pancreatitismentioning

confidence: 99%

Section: Lysosomal Dysfunction and Impaired Autophagy In Pancreatitismentioning

confidence: 99%

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confidence: 99%

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Organellar Dysfunction in the Pathogenesis of Pancreatitis

Gukovsky

Pandol

Gukovskaya

2011

Antioxidants & Redox Signaling

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“…In addition, the lysosomal hydrolase cathepsin-L degrades trypsinogen to an inactive form of trypsin thus providing protection against premature zymogen activation. Paradoxically, when cathepsin-L is genetically deleted there is also a switch from acinar cell necrosis to apoptosis with reduced severity of disease (Wartmann et al, 2010). This indicates that cathepsin L may be involved in additional pathways which contribute to pancreatitis.…”

Section: Role Of Premature Trypsinogen Activationmentioning

confidence: 99%

“…The lysosomal hydrolase cathepsin-B prematurely converts the digestive zymogen, trypsinogen, to its active form, trypsin (Figarella et al, 1988;Gorelick and Matovcik, 1995;Lerch et al, 1995;Wartmann et al, 2010). This conversion requires an acidic pH and cathepsin-B activates trypsinogen in a pH dependent manner (Kukor et al, 2002).…”

Section: Role Of Premature Trypsinogen Activationmentioning

confidence: 99%

Risk Factors for Pancreatic Cancer: Underlying Mechanisms and Potential Targets

2015

Frontiers Research Topics

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Purpose of the review: Pancreatic cancer is extremely aggressive, forming highly chemo-resistant tumors, and has one of the worst prognoses. The evolution of this cancer is multi-factorial. Repeated acute pancreatic injury and inflammation are important contributing factors in the development of pancreatic cancer. This article attempts to understand the common pathways linking pancreatitis to pancreatic cancer.Recent findings: Intracellular activation of both pancreatic enzymes and the transcription factor NF-κB are important mechanisms that induce acute pancreatitis (AP). Recurrent pancreatic injury due to genetic susceptibility, environmental factors such as smoking, alcohol intake, and conditions such as obesity lead to increases in oxidative stress, impaired autophagy and constitutive activation of inflammatory pathways. These processes can stimulate pancreatic stellate cells, thereby increasing fibrosis and encouraging chronic disease development. Activation of oncogenic Kras mutations through inflammation, coupled with altered levels of tumor suppressor proteins (p53 and p16) can ultimately lead to development of pancreatic cancer.Summary: Although our understanding of pancreatitis and pancreatic cancer has tremendously increased over many years, much remains to be elucidated in terms of common pathways linking these conditions.

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