MMP-9 Deficiency Enhances Collagenase-Induced Intracerebral Hemorrhage and Brain Injury in Mutant Mice

Abstract

Summary:Matrix metalloproteinase-9 (MMP-9) participates in the disregulation of blood-brain barrier during hemorrhagic transformation, and exacerbates brain injury after cerebral ischemia. However, the consequences of long-term inhibition or deficiency of MMP-9 activity (which might affect normal collagen or matrix homeostasis) remains to be determined. The authors investigated how MMP-9 gene deficiency enhances hemorrhage and increases mortality and neurologic deficits in a collagenase-induced intracerebral hemorrhage (ICH) model in MMP-9-knockout mice. MMP-9-knockout and corresponding wild-type mice at 20 to 35 weeks were used to model an aged population (because advanced age is a significant risk factor in human ICH). Collagenase VII-S (0.5 L, 0.075 U) was injected into the right basal ganglia in mice and mortality, neurologic deficits, brain edema, and hemorrhage size measured. In addition, MMP-9 activity, brain collagen content, blood coagulation, cerebral arterial structure, and expressions of several MMPs were examined. Increased hemorrhage and brain edema that correlated with higher mortality and neurologic deficits were found in MMP-9-knockout mice. No apparent structural changes were observed in cerebral arteries, even though brain collagen content was reduced in MMP-9-knockout mice. MMP-9-knockout mice did exhibit an enhanced expression of MMP-2 and MMP-3 in response to ICH. The results indicate that a deficiency of MMP-9 gene in mutant mice increases collagenase-induced hemorrhage and the resulting brain injury. The intriguing relationship between MMP-9 deficiency and collagenase-induced ICH may reflect the reduction in collagen content and an enhanced expression of MMP-2 and MMP-3. Key Words: MMP-9-Intracerebral hemorrhage-Collagenase-Edema-Blood-brain barrier-Coagulation.Spontaneous intracerebral hemorrhage (ICH) is one of the most serious stroke events, and results in high mortality and morbidity in patients (Bernardini and DeShaies, 2001;Panagos et al., 2002;Woo and Broderick, 2002). Mortality in ICH is often as high as 50% within the first month after ICH, with 50% of these deaths occurring within 48 hours (Broderick, 1993). The mechanisms of ICH-induced early brain injury (e.g. brain edema) have been investigated (Altumbabic et al., 1998;Del Bigio et al., 1999;Xi et al., 2002); however, the complete etiology of early brain injury in ICH is incompletely understood.Matrix metalloproteinases (MMPs) are involved in the pathogenesis of cerebral vascular disorders, particularly the formation and rupture of aneurysms. For example, pro-MMP-2 has been implicated as a significant component within arterial walls of intracerebral aneurysms that leads to subarachnoid hemorrhage (Todor et al., 1998). Other studies also support elevated MMP (elastase and collagenase) activity in ruptured vessels in subarachnoid hemorrhage but not in unruptured aneurysms (Gaetani et al., 1999). MMPs are also involved in the hemorrhagic transformation after cerebral ischemia, especially after thrombolysis (Hosomi et al., 2001;M...

Matrix Metalloproteinase Regulation in Intracerebral Hemorrhage

“…Rats injected with MMP-9 siRNA on days 7 and 10 following collagenase-induced ICH showed decreased neurogenesis and functional recovery [70] . These results appear to corroborate the findings of Tang et al, who showed that MMP-9 knockout mice had increased hemorrhage, brain edema, early neurobehavioral deficits, and mortality in collagenase-induced ICH [71] . However, this paradoxical effect of MMP-9 inhibition in a subacute time frame may actually highlight a dual purpose for MMP expression: a pathological acute phase that contributes to inflammation and cell death and a subacute neuroprotective phase highlighted by angiogenesis [72] .…”

Lack of matrix metalloproteinase-9 worsens ventilator-induced lung injury

“…It has been reported that expression of MMP-9 improves airway epithelial wound repair (5), so a direct effect of this metalloprotease in keeping the epithelial integrity or in the extracellular matrix could be considered. In a very different experiment, lack of MMP-9 was associated with a worse outcome and more brain injury after collagenase-induced brain hemorrhage (43). Vascular injury during mechanical ventilation is another mechanism of VILI, so the role of MMP-9 in the maintenance of the vascular wall should be taken into account.…”

“…However, nonselective inhibitors can modify the activity of other enzymes, precluding any firm conclusion on the specific role of MMP-9. Moreover, studies with mice lacking MMP-9 have shown that this enzyme is essential for an adequate inflammatory response and tissue repair, as these animals have an increased lung damage after the induction of peritonitis (39) and a poor outcome after an experimental brain hemorrhage (43).…”

Exploring Neuroprotective Drug Therapies for Intracerebral Hemorrhage

“…For example, a study on MMP-9-deficient mice showed that collagenase injection into the striatum of the mutant mice resulted in enhanced bleeding, increased mortality, and exacerbated neurological deficits. These changes may be attributable to heightened expression of MMP-2 and MMP-3 in response to ICH, together with lowered levels of collagen in the brain of MMP-9-deficient mice (22). In addition, systemic administration of BB-94, a broad spectrum MMP inhibitor, from 30 min before collagenase injection increased hemorrhagic volume and the number of cells exhibiting DNA fragmentation (23).…”