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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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MMP9−/−:Plg−/− mice develop large inflammatory mass lesions in the colon, mimicking prolapsed mucosa in humans. Dissection of MMP9−/−:Plg−/− mice revealed that large pedunculated tumorous lesions occupied the colon lumen, resulting in complete obstruction of fecal flow. By contrast, macroscopic inspection of Plg−/− mice only revealed smaller abnormalities in a fraction of the investigated mice. (A) A representative picture of intestines isolated from an MMP9−/−:Plg−/− mouse, in which blockade of the colon resulted in the accumulation of feces in the proximal colon (including the cecum) and even the ileum. Inset shows the solid tumor that was visible after removal of the distal colon while the dilated proximal colon is still attached. (B) Dissection of a colon from an MMP9−/−:Plg−/− mouse revealed a pedunculated tumorous lesion as well as smaller inflammatory lesions located proximal to the obstructing mass lesion. (C) In a time-course study, colons were isolated from WT, MMP9−/−, Plg−/− and MMP9−/−:Plg−/− mice at the age of 8 and 12 weeks, and at the time point at which they had to be euthanized owing to ethical considerations (between the age of 19 and 26 weeks). Colons were classified as normal, abnormal or containing a bulky tumorous lesion. ‘Abnormal’ refers to small hyperplastic lesions in the mucosal wall and ‘bulky tumorous lesion’ refers to the presence of at least one large obstructing mass lesion. All WT and MMP9−/− mice appeared normal and were thus not included in the graph. The graph shows the fraction of the mice in each group expressing the three different phenotypes. (D) Microscopic scanning of a large obstructing mass lesion covered by a broad pseudomembrane (arrow 1). The subjacent mucosa displayed a markedly distorted crypt pattern, including several cystically dilated and angulated crypts (arrow 2). Remnants of a lymphoid follicle occupied the superficial portion of the submucosa (arrow 3). (E) Close-up view of the boxed area in D illustrates the streaming pattern of inflammatory cells in the mucinous material of the pseudomembrane (arrow 1). Additionally, inflammatory cells expanded the surrounding lamina propria and extended for a limited distance into the subjacent submucosa (arrow 2). (F,G) Small lesions in 8-week-old MMP9−/−:Plg−/− mice were closely associated with enlarged lymphoid follicles. These lesions are speculated to develop into the inflammatory mass lesions over time. (H,I) Lesions in 12-week-old MMP9−/−:Plg−/− mice have now reached a considerable size and recruitment of additional inflammatory cells was evident along with some distortion of the associated crypt pattern surrounding the lesions. Scale bars: 1 mm (D); 200 μm (F–I).
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f2-0040212: MMP9−/−:Plg−/− mice develop large inflammatory mass lesions in the colon, mimicking prolapsed mucosa in humans. Dissection of MMP9−/−:Plg−/− mice revealed that large pedunculated tumorous lesions occupied the colon lumen, resulting in complete obstruction of fecal flow. By contrast, macroscopic inspection of Plg−/− mice only revealed smaller abnormalities in a fraction of the investigated mice. (A) A representative picture of intestines isolated from an MMP9−/−:Plg−/− mouse, in which blockade of the colon resulted in the accumulation of feces in the proximal colon (including the cecum) and even the ileum. Inset shows the solid tumor that was visible after removal of the distal colon while the dilated proximal colon is still attached. (B) Dissection of a colon from an MMP9−/−:Plg−/− mouse revealed a pedunculated tumorous lesion as well as smaller inflammatory lesions located proximal to the obstructing mass lesion. (C) In a time-course study, colons were isolated from WT, MMP9−/−, Plg−/− and MMP9−/−:Plg−/− mice at the age of 8 and 12 weeks, and at the time point at which they had to be euthanized owing to ethical considerations (between the age of 19 and 26 weeks). Colons were classified as normal, abnormal or containing a bulky tumorous lesion. ‘Abnormal’ refers to small hyperplastic lesions in the mucosal wall and ‘bulky tumorous lesion’ refers to the presence of at least one large obstructing mass lesion. All WT and MMP9−/− mice appeared normal and were thus not included in the graph. The graph shows the fraction of the mice in each group expressing the three different phenotypes. (D) Microscopic scanning of a large obstructing mass lesion covered by a broad pseudomembrane (arrow 1). The subjacent mucosa displayed a markedly distorted crypt pattern, including several cystically dilated and angulated crypts (arrow 2). Remnants of a lymphoid follicle occupied the superficial portion of the submucosa (arrow 3). (E) Close-up view of the boxed area in D illustrates the streaming pattern of inflammatory cells in the mucinous material of the pseudomembrane (arrow 1). Additionally, inflammatory cells expanded the surrounding lamina propria and extended for a limited distance into the subjacent submucosa (arrow 2). (F,G) Small lesions in 8-week-old MMP9−/−:Plg−/− mice were closely associated with enlarged lymphoid follicles. These lesions are speculated to develop into the inflammatory mass lesions over time. (H,I) Lesions in 12-week-old MMP9−/−:Plg−/− mice have now reached a considerable size and recruitment of additional inflammatory cells was evident along with some distortion of the associated crypt pattern surrounding the lesions. Scale bars: 1 mm (D); 200 μm (F–I).

Mentions: Necropsy of MMP9−/−:Plg−/− mice revealed a completely unanticipated phenotype characterized by the formation of severe inflammatory mass lesions in the colon. Macroscopically these mass lesions appeared as large obstructing tumors, which in all cases developed near the same location at the upper part of the sigmoid colon, and resulted in proximal distention of the colon, cecum and small intestines owing to a complete blockade of the bowel lumen (Fig. 2A,B). The volume of these tumorous mass lesions ranged from approximately 50–250 mm3. In some cases, they were associated with several smaller mass lesions proximal to the central mass lesion. The tissue between these smaller mass lesions seemed normal. Gross inspection of the lesions, colon and feces did not reveal any signs of hemorrhage or perforation of the colon. In some cases, the mass lesions were pedunculated, whereas in others they had a more flattened appearance. Examination of mice euthanized at various time points revealed that the formation of these mass lesions in MMP9−/−:Plg−/− mice commenced around the age of 12 weeks, at which time point 20% of the mice (0/6 males and 3/9 females) carried tumors. At an average age of approximately 24 weeks, 85% of the MMP9−/−:Plg−/− mice (5/5 males and 6/8 females) had developed large and obstructing inflammatory mass lesions in their colons, whereas only a single Plg−/− mouse (0/7 males and 1/9 females) showed signs of having such an inflammatory mass lesion in the colon (Fig. 2C). No WT or MMP9−/− mice developed any signs of colon abnormalities.


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)

MMP9−/−:Plg−/− mice develop large inflammatory mass lesions in the colon, mimicking prolapsed mucosa in humans. Dissection of MMP9−/−:Plg−/− mice revealed that large pedunculated tumorous lesions occupied the colon lumen, resulting in complete obstruction of fecal flow. By contrast, macroscopic inspection of Plg−/− mice only revealed smaller abnormalities in a fraction of the investigated mice. (A) A representative picture of intestines isolated from an MMP9−/−:Plg−/− mouse, in which blockade of the colon resulted in the accumulation of feces in the proximal colon (including the cecum) and even the ileum. Inset shows the solid tumor that was visible after removal of the distal colon while the dilated proximal colon is still attached. (B) Dissection of a colon from an MMP9−/−:Plg−/− mouse revealed a pedunculated tumorous lesion as well as smaller inflammatory lesions located proximal to the obstructing mass lesion. (C) In a time-course study, colons were isolated from WT, MMP9−/−, Plg−/− and MMP9−/−:Plg−/− mice at the age of 8 and 12 weeks, and at the time point at which they had to be euthanized owing to ethical considerations (between the age of 19 and 26 weeks). Colons were classified as normal, abnormal or containing a bulky tumorous lesion. ‘Abnormal’ refers to small hyperplastic lesions in the mucosal wall and ‘bulky tumorous lesion’ refers to the presence of at least one large obstructing mass lesion. All WT and MMP9−/− mice appeared normal and were thus not included in the graph. The graph shows the fraction of the mice in each group expressing the three different phenotypes. (D) Microscopic scanning of a large obstructing mass lesion covered by a broad pseudomembrane (arrow 1). The subjacent mucosa displayed a markedly distorted crypt pattern, including several cystically dilated and angulated crypts (arrow 2). Remnants of a lymphoid follicle occupied the superficial portion of the submucosa (arrow 3). (E) Close-up view of the boxed area in D illustrates the streaming pattern of inflammatory cells in the mucinous material of the pseudomembrane (arrow 1). Additionally, inflammatory cells expanded the surrounding lamina propria and extended for a limited distance into the subjacent submucosa (arrow 2). (F,G) Small lesions in 8-week-old MMP9−/−:Plg−/− mice were closely associated with enlarged lymphoid follicles. These lesions are speculated to develop into the inflammatory mass lesions over time. (H,I) Lesions in 12-week-old MMP9−/−:Plg−/− mice have now reached a considerable size and recruitment of additional inflammatory cells was evident along with some distortion of the associated crypt pattern surrounding the lesions. Scale bars: 1 mm (D); 200 μm (F–I).
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Related In: Results  -  Collection

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f2-0040212: MMP9−/−:Plg−/− mice develop large inflammatory mass lesions in the colon, mimicking prolapsed mucosa in humans. Dissection of MMP9−/−:Plg−/− mice revealed that large pedunculated tumorous lesions occupied the colon lumen, resulting in complete obstruction of fecal flow. By contrast, macroscopic inspection of Plg−/− mice only revealed smaller abnormalities in a fraction of the investigated mice. (A) A representative picture of intestines isolated from an MMP9−/−:Plg−/− mouse, in which blockade of the colon resulted in the accumulation of feces in the proximal colon (including the cecum) and even the ileum. Inset shows the solid tumor that was visible after removal of the distal colon while the dilated proximal colon is still attached. (B) Dissection of a colon from an MMP9−/−:Plg−/− mouse revealed a pedunculated tumorous lesion as well as smaller inflammatory lesions located proximal to the obstructing mass lesion. (C) In a time-course study, colons were isolated from WT, MMP9−/−, Plg−/− and MMP9−/−:Plg−/− mice at the age of 8 and 12 weeks, and at the time point at which they had to be euthanized owing to ethical considerations (between the age of 19 and 26 weeks). Colons were classified as normal, abnormal or containing a bulky tumorous lesion. ‘Abnormal’ refers to small hyperplastic lesions in the mucosal wall and ‘bulky tumorous lesion’ refers to the presence of at least one large obstructing mass lesion. All WT and MMP9−/− mice appeared normal and were thus not included in the graph. The graph shows the fraction of the mice in each group expressing the three different phenotypes. (D) Microscopic scanning of a large obstructing mass lesion covered by a broad pseudomembrane (arrow 1). The subjacent mucosa displayed a markedly distorted crypt pattern, including several cystically dilated and angulated crypts (arrow 2). Remnants of a lymphoid follicle occupied the superficial portion of the submucosa (arrow 3). (E) Close-up view of the boxed area in D illustrates the streaming pattern of inflammatory cells in the mucinous material of the pseudomembrane (arrow 1). Additionally, inflammatory cells expanded the surrounding lamina propria and extended for a limited distance into the subjacent submucosa (arrow 2). (F,G) Small lesions in 8-week-old MMP9−/−:Plg−/− mice were closely associated with enlarged lymphoid follicles. These lesions are speculated to develop into the inflammatory mass lesions over time. (H,I) Lesions in 12-week-old MMP9−/−:Plg−/− mice have now reached a considerable size and recruitment of additional inflammatory cells was evident along with some distortion of the associated crypt pattern surrounding the lesions. Scale bars: 1 mm (D); 200 μm (F–I).
Mentions: Necropsy of MMP9−/−:Plg−/− mice revealed a completely unanticipated phenotype characterized by the formation of severe inflammatory mass lesions in the colon. Macroscopically these mass lesions appeared as large obstructing tumors, which in all cases developed near the same location at the upper part of the sigmoid colon, and resulted in proximal distention of the colon, cecum and small intestines owing to a complete blockade of the bowel lumen (Fig. 2A,B). The volume of these tumorous mass lesions ranged from approximately 50–250 mm3. In some cases, they were associated with several smaller mass lesions proximal to the central mass lesion. The tissue between these smaller mass lesions seemed normal. Gross inspection of the lesions, colon and feces did not reveal any signs of hemorrhage or perforation of the colon. In some cases, the mass lesions were pedunculated, whereas in others they had a more flattened appearance. Examination of mice euthanized at various time points revealed that the formation of these mass lesions in MMP9−/−:Plg−/− mice commenced around the age of 12 weeks, at which time point 20% of the mice (0/6 males and 3/9 females) carried tumors. At an average age of approximately 24 weeks, 85% of the MMP9−/−:Plg−/− mice (5/5 males and 6/8 females) had developed large and obstructing inflammatory mass lesions in their colons, whereas only a single Plg−/− mouse (0/7 males and 1/9 females) showed signs of having such an inflammatory mass lesion in the colon (Fig. 2C). No WT or MMP9−/− mice developed any signs of colon abnormalities.

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