RGD Reference Report - Inhibition of matrix metalloproteinase-9 with doxycycline reduces pancreatitis-associated lung injury. - Rat Genome Database

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Inhibition of matrix metalloproteinase-9 with doxycycline reduces pancreatitis-associated lung injury.

Authors: Sochor, M  Richter, S  Schmidt, A  Hempel, S  Hopt, UT  Keck, T 
Citation: Sochor M, etal., Digestion. 2009;80(2):65-73. Epub 2009 Jun 3.
RGD ID: 5129548
Pubmed: PMID:19494493   (View Abstract at PubMed)
DOI: DOI:10.1159/000212080   (Journal Full-text)

BACKGROUND/AIMS: Severe lung injury, responsible for up to 15% of mortality in acute necrotizing pancreatitis patients, is promoted by neutrophil (PMN) migration into the lung. We have previously demonstrated that pulmonary injury in acute pancreatitis is mediated by PMN-derived matrix metalloproteinase-9 (MMP-9). This study was conducted to evaluate the ability of the broad-spectrum MMP inhibitor doxycycline to prevent secondary pulmonary injury in acute pancreatitis. METHODS: Eighteen rats were randomized into three groups: severe pancreatitis (SAP), severe pancreatitis + doxycycline (SAP+Dox) (30 mg/kg body mass) or control. Acute pancreatitis was induced by intraductal glycodesoxycholic acid and i.v. stimulation with cerulein. Lung sections were histologically graded for edema, microthrombi, atelectasis and hemorrhage. Active MMP-9 in lung tissue was measured with fluorescent assay (ELISA). Naphtol-AS-D-chloroacetate esterase staining was used to determine pulmonary PMN infiltration. The inhibitory effect of doxycycline on MMP-9-induced transmigration was confirmed in a Matrigel transmigration assay. RESULTS: Addition of doxycycline significantly reduced TNF-alpha-induced PMN transmigration across Matrigel membrane (12.6 +/- 2.6 vs. 20.1 +/- 3.9 PMNs; p < 0.05). SAP+Dox showed decreased concentration of active MMP-9 in lung tissue (37.89 +/- 1.75 vs. 46.29 +/- 3.68 ng/ml; p < 0.05) and as a result decreased pulmonary infiltration of PMNs (21.2 +/- 5.1 vs. 32.5 +/- 6.8; p < 0.05). Histological evaluation revealed decreased pulmonary edema (1.83 +/- 0.41 vs. 2.33 +/- 0.51, p < 0.05), atelectasis (1.67 +/- 0.52 vs. 2.33 +/- 0.52; p < 0.05) and pulmonary hemorrhage (2.5 +/- 0.55 vs. 1.83 +/- 0.41; p < 0.05) in SAP+Dox vs. SAP. These findings were paralleled by reduced pulmonary expression of active MMP-9. CONCLUSIONS: Inhibition of MMP-9 activity with doxycycline reduced pancreatitis-associated lung injury and expression of MMP-9 in pulmonary tissue. Doxycycline reduced PMN migration in vitro and in vivo and therefore might represent a novel strategy for the prevention of secondary pulmonary complications in acute pancreatitis.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
lung disease  ISOMmp9 (Rattus norvegicus)5129548; 5129548lung injury associated with pancreatitis and acute necrotizingRGD 
lung disease  IMP 5129548lung injury associated with pancreatitis and acute necrotizingRGD 

Objects Annotated

Genes (Rattus norvegicus)
Mmp9  (matrix metallopeptidase 9)

Genes (Mus musculus)
Mmp9  (matrix metallopeptidase 9)

Genes (Homo sapiens)
MMP9  (matrix metallopeptidase 9)


Additional Information