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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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Fibrin depositions trigger the development of inflammatory mass lesions in MMP9−/−:Plg−/− mice. (A,B) Microscopic lesions in 8- and 12-week-old Plg−/− mice, showing that lesions in these mice also grow with increasing age and are associated with fibrin depositions (arrows indicate fibrin depositions). (C,D) Similar to Plg−/− mice, MMP9−/−:Plg−/− mice develop lesions in association with fibrin depositions (arrows) but, by contrast, these lesions are several-fold larger and the inflammatory reactions expand laterally away from the deposited fibrin for a considerable distance. Notice the large inflammatory follicular structure already present at 8 weeks of age. (E,F) Fibrin depositions were not a general feature of the inflammatory mass lesions in MMP9−/−:Plg−/− mice older than 19 weeks, although small restricted areas with accumulated fibrin in the lamina propria could be detected. (G–I) Staining for granulocytes using anti-Gr1 antibodies showed that the healthy part of the colon mucosa (H) contained very few granulocytes, whereas, in the inflammatory mass lesion (G,I), an abundant presence of granulocytes was found both in the submucosa and the lamina propria (arrow indicates beginning of a mass lesion). (J,K) A high level of MMP9 expression was found in the inflamed mucosa surrounding the microscopic lesions in Plg−/− mice. The expression was confined to inflammatory cells in the lamina propria, whereas epithelial cells were devoid of MMP9 staining (the arrow indicates the lesion site). (L,M) Macrophage staining with anti-CD204 antibodies revealed that some of the inflammatory mass lesions in MMP9−/−:Plg−/− mice contain macrophages in the superficial portion of the mucosa as well as in some of the expanded crypts. (N–Q) Another macrophage marker, F4/80, confirmed that the number of macrophages varied between mass lesions in different MMP9−/−:Plg−/− mice and also within each lesion. An example of a low-F4/80-expressing lesion is provided in N and O, and a representative staining of a high-F4/80-expressing lesion is provided in P and Q.
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f3-0040212: Fibrin depositions trigger the development of inflammatory mass lesions in MMP9−/−:Plg−/− mice. (A,B) Microscopic lesions in 8- and 12-week-old Plg−/− mice, showing that lesions in these mice also grow with increasing age and are associated with fibrin depositions (arrows indicate fibrin depositions). (C,D) Similar to Plg−/− mice, MMP9−/−:Plg−/− mice develop lesions in association with fibrin depositions (arrows) but, by contrast, these lesions are several-fold larger and the inflammatory reactions expand laterally away from the deposited fibrin for a considerable distance. Notice the large inflammatory follicular structure already present at 8 weeks of age. (E,F) Fibrin depositions were not a general feature of the inflammatory mass lesions in MMP9−/−:Plg−/− mice older than 19 weeks, although small restricted areas with accumulated fibrin in the lamina propria could be detected. (G–I) Staining for granulocytes using anti-Gr1 antibodies showed that the healthy part of the colon mucosa (H) contained very few granulocytes, whereas, in the inflammatory mass lesion (G,I), an abundant presence of granulocytes was found both in the submucosa and the lamina propria (arrow indicates beginning of a mass lesion). (J,K) A high level of MMP9 expression was found in the inflamed mucosa surrounding the microscopic lesions in Plg−/− mice. The expression was confined to inflammatory cells in the lamina propria, whereas epithelial cells were devoid of MMP9 staining (the arrow indicates the lesion site). (L,M) Macrophage staining with anti-CD204 antibodies revealed that some of the inflammatory mass lesions in MMP9−/−:Plg−/− mice contain macrophages in the superficial portion of the mucosa as well as in some of the expanded crypts. (N–Q) Another macrophage marker, F4/80, confirmed that the number of macrophages varied between mass lesions in different MMP9−/−:Plg−/− mice and also within each lesion. An example of a low-F4/80-expressing lesion is provided in N and O, and a representative staining of a high-F4/80-expressing lesion is provided in P and Q.

Mentions: The microscopic lesions in 8- and 12-week-old MMP9−/−:Plg−/−mice were clearly stained positive for fibrin depositions, and the presence of these depositions seemed to be directly associated with an inflammatory response (Fig. 3A–D). Surprisingly, fibrin depositions were not a general feature of the obstructing inflammatory mass lesion found in the older mice, although a few scattered areas in the conspicuous lamina propria did stain positive for fibrin (Fig. 3E,F).


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)

Fibrin depositions trigger the development of inflammatory mass lesions in MMP9−/−:Plg−/− mice. (A,B) Microscopic lesions in 8- and 12-week-old Plg−/− mice, showing that lesions in these mice also grow with increasing age and are associated with fibrin depositions (arrows indicate fibrin depositions). (C,D) Similar to Plg−/− mice, MMP9−/−:Plg−/− mice develop lesions in association with fibrin depositions (arrows) but, by contrast, these lesions are several-fold larger and the inflammatory reactions expand laterally away from the deposited fibrin for a considerable distance. Notice the large inflammatory follicular structure already present at 8 weeks of age. (E,F) Fibrin depositions were not a general feature of the inflammatory mass lesions in MMP9−/−:Plg−/− mice older than 19 weeks, although small restricted areas with accumulated fibrin in the lamina propria could be detected. (G–I) Staining for granulocytes using anti-Gr1 antibodies showed that the healthy part of the colon mucosa (H) contained very few granulocytes, whereas, in the inflammatory mass lesion (G,I), an abundant presence of granulocytes was found both in the submucosa and the lamina propria (arrow indicates beginning of a mass lesion). (J,K) A high level of MMP9 expression was found in the inflamed mucosa surrounding the microscopic lesions in Plg−/− mice. The expression was confined to inflammatory cells in the lamina propria, whereas epithelial cells were devoid of MMP9 staining (the arrow indicates the lesion site). (L,M) Macrophage staining with anti-CD204 antibodies revealed that some of the inflammatory mass lesions in MMP9−/−:Plg−/− mice contain macrophages in the superficial portion of the mucosa as well as in some of the expanded crypts. (N–Q) Another macrophage marker, F4/80, confirmed that the number of macrophages varied between mass lesions in different MMP9−/−:Plg−/− mice and also within each lesion. An example of a low-F4/80-expressing lesion is provided in N and O, and a representative staining of a high-F4/80-expressing lesion is provided in P and Q.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f3-0040212: Fibrin depositions trigger the development of inflammatory mass lesions in MMP9−/−:Plg−/− mice. (A,B) Microscopic lesions in 8- and 12-week-old Plg−/− mice, showing that lesions in these mice also grow with increasing age and are associated with fibrin depositions (arrows indicate fibrin depositions). (C,D) Similar to Plg−/− mice, MMP9−/−:Plg−/− mice develop lesions in association with fibrin depositions (arrows) but, by contrast, these lesions are several-fold larger and the inflammatory reactions expand laterally away from the deposited fibrin for a considerable distance. Notice the large inflammatory follicular structure already present at 8 weeks of age. (E,F) Fibrin depositions were not a general feature of the inflammatory mass lesions in MMP9−/−:Plg−/− mice older than 19 weeks, although small restricted areas with accumulated fibrin in the lamina propria could be detected. (G–I) Staining for granulocytes using anti-Gr1 antibodies showed that the healthy part of the colon mucosa (H) contained very few granulocytes, whereas, in the inflammatory mass lesion (G,I), an abundant presence of granulocytes was found both in the submucosa and the lamina propria (arrow indicates beginning of a mass lesion). (J,K) A high level of MMP9 expression was found in the inflamed mucosa surrounding the microscopic lesions in Plg−/− mice. The expression was confined to inflammatory cells in the lamina propria, whereas epithelial cells were devoid of MMP9 staining (the arrow indicates the lesion site). (L,M) Macrophage staining with anti-CD204 antibodies revealed that some of the inflammatory mass lesions in MMP9−/−:Plg−/− mice contain macrophages in the superficial portion of the mucosa as well as in some of the expanded crypts. (N–Q) Another macrophage marker, F4/80, confirmed that the number of macrophages varied between mass lesions in different MMP9−/−:Plg−/− mice and also within each lesion. An example of a low-F4/80-expressing lesion is provided in N and O, and a representative staining of a high-F4/80-expressing lesion is provided in P and Q.
Mentions: The microscopic lesions in 8- and 12-week-old MMP9−/−:Plg−/−mice were clearly stained positive for fibrin depositions, and the presence of these depositions seemed to be directly associated with an inflammatory response (Fig. 3A–D). Surprisingly, fibrin depositions were not a general feature of the obstructing inflammatory mass lesion found in the older mice, although a few scattered areas in the conspicuous lamina propria did stain positive for fibrin (Fig. 3E,F).

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