Format

Send to

Choose Destination
See comment in PubMed Commons below
Gastroenterology. 2010 Jun;138(7):2531-40, 2540.e1-4. doi: 10.1053/j.gastro.2010.02.043. Epub 2010 Feb 23.

Pancreas-specific ablation of beta1 integrin induces tissue degeneration by disrupting acinar cell polarity.

Author information

1
Department of Pharmacology, Stony Brook University, Stony Brook, New York 11794-8651, USA.

Abstract

BACKGROUND & AIMS:

Integrin contact with basement membrane is a major determinant of epithelial cell polarity. beta1 integrin heterodimers are the primary receptors for basement membrane in pancreatic acinar cells, which function to synthesize and directionally secrete digestive enzymes into a central lumen. Aberrant acinar secretion and exposure of the parenchyma to digestive enzyme activity lead to organ damage and pancreatitis.

METHODS:

beta1 integrin conditional knockout mice were crossed to Ptf1a-Cre mice to ablate beta1 integrin in the pancreas. Histopathology of aged and cerulein-treated mice were assessed by histology and immunocytochemistry. Directional secretion was determined in vitro by FM1-43 loading with cerulein stimulation.

RESULTS:

Pancreas-specific ablation of beta1 integrin led to progressive organ degeneration, associated with focal acinar cell necrosis and ductal metaplasia along with widespread inflammation and collagen deposition. beta1 Integrin-null pancreata were highly susceptible to cerulein-induced acute pancreatitis, displaying an enhanced level of damage with no loss in regeneration. Degenerating beta1 integrin-null pancreata were marked by disruption of acinar cell polarity. Protein kinase C epsilon, normally localized apically, was found in the cytoplasm where it can lead to intracellular digestive enzyme activation. beta1 Integrin-null acinar cells displayed indiscriminate secretion to all membrane surfaces, consistent with an observed loss of basolateral membrane localization of Munc18c, which normally prevents basal secretion of digestive enzymes.

CONCLUSIONS:

Ablation of beta1 integrin induces organ atrophy by disrupting acinar cell polarity and exposing the pancreatic parenchyma to digestive enzymes.

PMID:
20188101
PMCID:
PMC2883624
DOI:
10.1053/j.gastro.2010.02.043
[Indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Elsevier Science Icon for PubMed Central
    Loading ...
    Support Center