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MMP9 is protective against lethal inflammatory mass lesions in the mouse colon.

Hald A, Rønø B, Melander MC, Ding M, Holck S, Lund LR - Dis Model Mech (2010)

Bottom Line: It has been speculated that this results from a functional overlap between individual MMPs and (as-yet-unclassified) functional overlaps between MMPs and other protease systems.These lesions possessed several histological attributes that are characteristic of mucosal prolapse seen in humans, and they were found to be associated with splenomegaly, enlarged mesenteric lymph nodes, decreased thymus size and altered populations of circulating immune cells.These data demonstrate a non-appreciated vital protective role for MMP9 in the absence of Plg.

View Article: PubMed Central - PubMed

Affiliation: Department of Cellular and Molecular Medicine, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark. ahald@sund.ku.dk

ABSTRACT
The family of matrix metalloproteinases (MMPs) is responsible for extracellular matrix degradation during physiological and pathophysiological tissue remodeling processes such as embryogenesis, tissue repair and cancer progression. Despite these important roles of MMPs, inhibition or ablation of individual members of the MMP family in animal models have been shown to have little effect. It has been speculated that this results from a functional overlap between individual MMPs and (as-yet-unclassified) functional overlaps between MMPs and other protease systems. We here present genetic data showing that concomitant ablation of MMP9 (gelatinase B) and the serine protease plasmin results in lethal inflammatory mass lesions in the colon. These lesions possessed several histological attributes that are characteristic of mucosal prolapse seen in humans, and they were found to be associated with splenomegaly, enlarged mesenteric lymph nodes, decreased thymus size and altered populations of circulating immune cells. A time-course study provided evidence that the massive lymphoid hyperplasia and reactive changes were secondary to discrete fibrinous lesions also observed in mice only deficient for plasminogen (Plg), the zymogen for plasmin. These data demonstrate a non-appreciated vital protective role for MMP9 in the absence of Plg.

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Enlargement of spleens and diminution of thymus in Plg−/− and MMP9−/−:Plg−/− mice with increasing age. (A) Spleens from Plg−/− and MMP9−/−:Plg−/−mice were enlarged compared with spleens derived from WT and MMP9−/− mice. (B) A weight graph based on formalin-fixed and dehydrated spleens isolated from mice at various time points shows that the spleens of Plg−/− and MMP9−/−:Plg−/− mice increase in weight as these mice start to develop rectal lesions or the inflammatory mass lesions in the colon. **P<0.01. (C) H&E staining revealed no unexpected pathological modifications in spleens isolated from mice carrying different genotypes compared with WT spleens (left panel). However, an increased number of granulocytes were present in spleens isolated from Plg−/− and MMP9−/−:Plg−/− mice compared with WT and MMP9−/− spleens (right panel). (D) Thymus in MMP9−/−:Plg−/− mice suffering from inflammatory mass lesions in the colon (right) were generally smaller than thymus isolated from Plg−/− mice, which, in turn, were smaller than thymus isolated from age-matched WT mice (left). (E) H&E stainings of thymus did not reveal any difference between the genotypes examined (top panels). However, fibrin staining revealed increased levels of fibrin in the thymus from Plg−/− mice compared with WT, and these levels were slightly increased in MMP9−/−:Plg−/− mice (bottom panels). For granulocyte analysis in spleen, n≥5. For fibrin analysis in thymus, n≥8.
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f5-0040212: Enlargement of spleens and diminution of thymus in Plg−/− and MMP9−/−:Plg−/− mice with increasing age. (A) Spleens from Plg−/− and MMP9−/−:Plg−/−mice were enlarged compared with spleens derived from WT and MMP9−/− mice. (B) A weight graph based on formalin-fixed and dehydrated spleens isolated from mice at various time points shows that the spleens of Plg−/− and MMP9−/−:Plg−/− mice increase in weight as these mice start to develop rectal lesions or the inflammatory mass lesions in the colon. **P<0.01. (C) H&E staining revealed no unexpected pathological modifications in spleens isolated from mice carrying different genotypes compared with WT spleens (left panel). However, an increased number of granulocytes were present in spleens isolated from Plg−/− and MMP9−/−:Plg−/− mice compared with WT and MMP9−/− spleens (right panel). (D) Thymus in MMP9−/−:Plg−/− mice suffering from inflammatory mass lesions in the colon (right) were generally smaller than thymus isolated from Plg−/− mice, which, in turn, were smaller than thymus isolated from age-matched WT mice (left). (E) H&E stainings of thymus did not reveal any difference between the genotypes examined (top panels). However, fibrin staining revealed increased levels of fibrin in the thymus from Plg−/− mice compared with WT, and these levels were slightly increased in MMP9−/−:Plg−/− mice (bottom panels). For granulocyte analysis in spleen, n≥5. For fibrin analysis in thymus, n≥8.

Mentions: During necropsy, a substantial enlargement of the spleen was observed in male Plg−/− and MMP9−/−:Plg−/− mice and female MMP9−/−:Plg−/− mice with increasing age of the animals. This increase was evident in male mice from the age of 12 weeks, whereas, in female mice, the increase in size was first evident at an age above 19 weeks (Fig. 5A,B). No difference was observed in the spleen size between male Plg−/− and MMP9−/−:Plg−/− mice. Histological examination of the spleens revealed a normal distribution and structure of the red and white pulp despite the increased size of the spleens (Fig. 5C). It was noted that both histological examinations and flow cytometric analyses [based on light side scatter (SSC)/forward scatter (FSC) profiling] showed that the concentration of granulocytes was elevated in the enlarged spleens (WT or MMP9−/− versus Plg−/− or MMP9−/−:Plg−/− mice), whereas the relative distribution of T cells and B cells seemed unaffected (Fig. 5C; supplementary material Fig. S7A,B). Further histological analyses showed that the number of F4/80-positive macrophages/mm2 in the red pulp was the same in WT, MMP9−/−, Plg−/− and MMP9−/−:Plg−/− mice (supplementary material Fig. S8).


MMP9 is protective against lethal inflammatory mass lesions in the mouse colon.

Hald A, Rønø B, Melander MC, Ding M, Holck S, Lund LR - Dis Model Mech (2010)

Enlargement of spleens and diminution of thymus in Plg−/− and MMP9−/−:Plg−/− mice with increasing age. (A) Spleens from Plg−/− and MMP9−/−:Plg−/−mice were enlarged compared with spleens derived from WT and MMP9−/− mice. (B) A weight graph based on formalin-fixed and dehydrated spleens isolated from mice at various time points shows that the spleens of Plg−/− and MMP9−/−:Plg−/− mice increase in weight as these mice start to develop rectal lesions or the inflammatory mass lesions in the colon. **P<0.01. (C) H&E staining revealed no unexpected pathological modifications in spleens isolated from mice carrying different genotypes compared with WT spleens (left panel). However, an increased number of granulocytes were present in spleens isolated from Plg−/− and MMP9−/−:Plg−/− mice compared with WT and MMP9−/− spleens (right panel). (D) Thymus in MMP9−/−:Plg−/− mice suffering from inflammatory mass lesions in the colon (right) were generally smaller than thymus isolated from Plg−/− mice, which, in turn, were smaller than thymus isolated from age-matched WT mice (left). (E) H&E stainings of thymus did not reveal any difference between the genotypes examined (top panels). However, fibrin staining revealed increased levels of fibrin in the thymus from Plg−/− mice compared with WT, and these levels were slightly increased in MMP9−/−:Plg−/− mice (bottom panels). For granulocyte analysis in spleen, n≥5. For fibrin analysis in thymus, n≥8.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3046095&req=5

f5-0040212: Enlargement of spleens and diminution of thymus in Plg−/− and MMP9−/−:Plg−/− mice with increasing age. (A) Spleens from Plg−/− and MMP9−/−:Plg−/−mice were enlarged compared with spleens derived from WT and MMP9−/− mice. (B) A weight graph based on formalin-fixed and dehydrated spleens isolated from mice at various time points shows that the spleens of Plg−/− and MMP9−/−:Plg−/− mice increase in weight as these mice start to develop rectal lesions or the inflammatory mass lesions in the colon. **P<0.01. (C) H&E staining revealed no unexpected pathological modifications in spleens isolated from mice carrying different genotypes compared with WT spleens (left panel). However, an increased number of granulocytes were present in spleens isolated from Plg−/− and MMP9−/−:Plg−/− mice compared with WT and MMP9−/− spleens (right panel). (D) Thymus in MMP9−/−:Plg−/− mice suffering from inflammatory mass lesions in the colon (right) were generally smaller than thymus isolated from Plg−/− mice, which, in turn, were smaller than thymus isolated from age-matched WT mice (left). (E) H&E stainings of thymus did not reveal any difference between the genotypes examined (top panels). However, fibrin staining revealed increased levels of fibrin in the thymus from Plg−/− mice compared with WT, and these levels were slightly increased in MMP9−/−:Plg−/− mice (bottom panels). For granulocyte analysis in spleen, n≥5. For fibrin analysis in thymus, n≥8.
Mentions: During necropsy, a substantial enlargement of the spleen was observed in male Plg−/− and MMP9−/−:Plg−/− mice and female MMP9−/−:Plg−/− mice with increasing age of the animals. This increase was evident in male mice from the age of 12 weeks, whereas, in female mice, the increase in size was first evident at an age above 19 weeks (Fig. 5A,B). No difference was observed in the spleen size between male Plg−/− and MMP9−/−:Plg−/− mice. Histological examination of the spleens revealed a normal distribution and structure of the red and white pulp despite the increased size of the spleens (Fig. 5C). It was noted that both histological examinations and flow cytometric analyses [based on light side scatter (SSC)/forward scatter (FSC) profiling] showed that the concentration of granulocytes was elevated in the enlarged spleens (WT or MMP9−/− versus Plg−/− or MMP9−/−:Plg−/− mice), whereas the relative distribution of T cells and B cells seemed unaffected (Fig. 5C; supplementary material Fig. S7A,B). Further histological analyses showed that the number of F4/80-positive macrophages/mm2 in the red pulp was the same in WT, MMP9−/−, Plg−/− and MMP9−/−:Plg−/− mice (supplementary material Fig. S8).

Bottom Line: It has been speculated that this results from a functional overlap between individual MMPs and (as-yet-unclassified) functional overlaps between MMPs and other protease systems.These lesions possessed several histological attributes that are characteristic of mucosal prolapse seen in humans, and they were found to be associated with splenomegaly, enlarged mesenteric lymph nodes, decreased thymus size and altered populations of circulating immune cells.These data demonstrate a non-appreciated vital protective role for MMP9 in the absence of Plg.

View Article: PubMed Central - PubMed

Affiliation: Department of Cellular and Molecular Medicine, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark. ahald@sund.ku.dk

ABSTRACT
The family of matrix metalloproteinases (MMPs) is responsible for extracellular matrix degradation during physiological and pathophysiological tissue remodeling processes such as embryogenesis, tissue repair and cancer progression. Despite these important roles of MMPs, inhibition or ablation of individual members of the MMP family in animal models have been shown to have little effect. It has been speculated that this results from a functional overlap between individual MMPs and (as-yet-unclassified) functional overlaps between MMPs and other protease systems. We here present genetic data showing that concomitant ablation of MMP9 (gelatinase B) and the serine protease plasmin results in lethal inflammatory mass lesions in the colon. These lesions possessed several histological attributes that are characteristic of mucosal prolapse seen in humans, and they were found to be associated with splenomegaly, enlarged mesenteric lymph nodes, decreased thymus size and altered populations of circulating immune cells. A time-course study provided evidence that the massive lymphoid hyperplasia and reactive changes were secondary to discrete fibrinous lesions also observed in mice only deficient for plasminogen (Plg), the zymogen for plasmin. These data demonstrate a non-appreciated vital protective role for MMP9 in the absence of Plg.

Show MeSH
Related in: MedlinePlus