Marianne Corbel

Role of gelatinases MMP-2 and MMP-9 in tissue remodeling following acute lung injury

Acute lung injury is characterized by a severe disruption of alveolo-capillary structures and includes a variety of changes in lung cell populations. Evidence suggests the occurrence of rupture of the basement membranes and interstitial matrix remodeling during acute lung injury. The dynamic equilibrium of the extracellular matrix (ECM) under physiological conditions is a consequence of the balance between the regulation of synthesis and degradation of ECM components. Matrix metalloproteinases (MMPs) represent a group of enzymes involved in the degradation of most of the components of the ECM and therefore participate in tissue remodeling associated with pathological situations such as acute lung injury. MMP activity is regulated by proteolytic activation of the latent secreted proenzyme and by interaction with specific tissue inhibitors of metalloproteinases. This review details our knowledge of the involvement of MMPs, namely MMP-2 and MMP-9, in acute lung injury and acute respiratory distress syndrome.

Involvement of gelatinases (MMP-2 and MMP-9) in the development of airway inflammation and pulmonary fibrosis

Pulmonary fibrosis has an aggressive course and is usually fatal an average of 3 to 6 years after the onset of symptoms. Pulmonary fibrosis is associated with deposition of extracellular matrix (ECM) components in the lung interstitium. Matrix metalloproteinases (MMPs) are a major group of proteinases known to regulate the ECM remodeling and so they are hypothesized to be important in the process of lung fibrosis. These led to the concept that modulation of airway remodeling including excessive proteolytic damage of the tissue may be of interest for future treatment. The excessive airway remodeling as a result of an imbalance in the equilibrium of the normal processes of synthesis and degradation of extracellular matrix components could argue in favor of antiprotease treatments. Moreover, these observations emphasize that effective therapies for these disorders must be given early in the natural history of the disease, prior to the development of expensive lung destruction and fibrosis.

Inhibition of bleomycin-induced pulmonary fibrosis in mice by the matrix metalloproteinase inhibitor batimastat.

Bleomycin‐induced pulmonary fibrosis is known to be associated with the increased activity of two gelatinases, matrix metalloproteinase (MMP)‐2 and MMP‐9, in bronchoalveolar lavage (BAL). This study has investigated the effect of a synthetic inhibitor of MMP, batimastat, on the development of pulmonary fibrosis induced by bleomycin administration in mice. Animals wereintranasally instilled with saline or bleomycin (0.5 mg in 100 µl per mouse). Batimastat (30 mg/kg) or vehicle alone was administered by intraperitoneal injection 24 h and 1 h before saline or bleomycin instillation, and then daily at the same dosage until the end of the study. Fifteen days after bleomycin administration, BAL was performed and the lung was removed. Treatment of mice with batimastat significantly reduced bleomycin‐induced lung fibrosis, as shown in the lung by histopathological examination and by a decrease in hydroxyproline levels. Batimastat also prevented the increase in BAL macrophage and lymphocyte numbers, whereas it did not show any effect on the increased expression of active transforming growth factor‐beta (TGF‐β) in BAL. Batimastat treatment was effective in reducing MMP‐2 and MMP‐9 activity as well as the tissue inhibitor of metalloproteinase‐1 (TIMP‐1) level in BAL. These results suggest that administration of the MMP inhibitor batimastat is useful in preventing experimental pulmonary fibrosis induced by bleomycin and raises the possibility of a therapeutic approach to human pulmonary fibrotic disease. Copyright

Effects of cannabinoid receptor ligands on LPS-induced pulmonary inflammation in mice

The effects of cannabinoid receptor agonists WIN 55,212-2, delta9-tetrahydrocannabinol (delta9-THC), arachidonoylethanolamide (anandamide) and palmitoylethanolamide on lipopolysaccharide (LPS) -induced bronchopulmonary inflammation in mice were investigated. WIN 55,212-2 and delta9-THC induced a concentration-dependent decrease in TNF-alpha level in the bronchoalveolar lavage fluid (BALF) (maximum inhibition 52.7% and 36.9% for intranasal doses of 750 nmol x kg(-1) and 2.65 mmol x kg(-1), respectively). This effect was accompanied by moderately reduced neutrophil recruitment. Palmitoylethanolamide (750 nmol x kg(-1)) diminished the level of TNF-alpha in BALF by 31.5% but had no effect on neutrophil recruitment. Anandamide (7.5-750 nmol x kg(-1)) did not influence the inflammatory process but TNF-alpha level and neutrophil recruitment were decreased by 28.0% and 62.0%, respectively, with 0.075 nmol x kg(-1). These results demonstrate that the cannabinoid receptor ligands inhibited LPS-induced pulmonary inflammation and suggest that this effect could be at least in part mediated by the cannabinoid CB2 receptor.

Imbalance between matrix metalloproteinases (MMP-9 and MMP-2) and tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2) in acute respiratory distress syndrome patients.

ObjectiveMatrix metalloproteinases (MMPs) are known to be involved in degradation of extracellular matrix. We aimed to assess the role of MMPs and their natural inhibitors (TIMPs) in the genesis and the evolution of acute respiratory distress syndrome (ARDS). DesignProspective, clinical study. SettingIntensive care unit of a university hospital. PatientsTwenty-one patients were assigned to three different groups: Group 1 patients developed ARDS that rapidly resolved in <4 days; Group 2 patients developed ARDS lasting >8 days; Group 3 (control group) patients had clinical criteria for hospital-acquired pneumonia without ARDS. InterventionBronchoalveolar lavages were performed on day 0 of the onset of ARDS and on days 4, 8, and 12 for unresolving ARDS. For group 3, the bronchoalveolar lavages were performed on day 0 of the pneumonia. On these bronchoalveolar lavage fluids, we measured the amount of MMP-9 and -2 and their inhibitors TIMP-1 and -2. Measurements and Main ResultsThe amount of MMP-9 measured by enzyme-linked immunosorbent assay was significantly lower in the bronchoalveolar lavages from patients with ARDS (group 1 and group 2) compared with the control group (p < .01) throughout the study. The ratio MMP-9/TIMP-1 was also significantly smaller and was less than one in the two ARDS groups (p < .05) compared with the control group (group 3), where this ratio was greater than one. In the second bronchoalveolar lavages, this ratio was greater than one only in the ARDS group that rapidly resolved (group 1), whereas it stayed less than one when the ARDS was lasting (group 2). Concerning the quantity of MMP-2 and the ratio MMP-2/TIMP-2, there was no statistical difference between the three groups throughout the study. Using zymography, there was no significant difference in the amounts of active and latent MMP-9 between the three groups. Moreover, no significant difference in the quantity of latent and active MMP-2 in the three groups was noted. ConclusionThese results suggest that the MMP-9 level and MMP-9/TIMP-1 ratio play a role in the pathogenesis of ARDS and, namely, the imbalance between MMP-9 and TIMP-1 would participate in airway remodeling leading to either short- or long-course ARDS. The ratio MMP-9/TIMP-1 could be a predictive factor of the ARDS evolution.

Repeated endotoxin exposure induces interstitial fibrosis associated with enhanced gelatinase (MMP-2 and MMP-9) activity

Abstract:Background: Dysregulation of matrix metalloproteinases (MMPs) has been implicated in lung injury associated with inflammatory disorders and several lung diseases such as pulmonary fibrosis.¶Objective: We studied a murine model of lipopolysaccharide (LPS)-induced chronic inflammation in order to analyse the relationship between MMP activity in bronchoalveolar lavage fluid and collagen deposition in lung tissue. BP2 mice were exposed to repeated aerosols of LPS of E. coli for 8 months.¶Results: The inflammatory reaction induced by LPS increased throughout the time of exposure and was associated after 10 weeks with collagen deposition in the alveolar walls. Meantime, we observed in BAL fluid from LPS-exposed mice an early induction of MMP-9 correlated with neutrophil recruitment. MMP-2 increased during the early inflammatory phase, and also during the development of the fibrotic phase.¶Conclusion: Repeated exposure of mice to an aerosol of LPS can lead to pulmonary interstitial fibrosis and MMPs seem to be associated with this process.¶

Modulation of airway remodeling-associated mediators by the antifibrotic compound, pirfenidone, and the matrix metalloproteinase inhibitor, batimastat, during acute lung injury in mice

Matrix metalloproteinases (MMPs) are potent to degrade basement membrane collagen associated with acute lung injury in inflammatory processes. We have investigated effects of pirfenidone, antifibrotic agent, and batimastat, inhibitor of MMPs, on gelatinase activities, on release of tumor necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta (TGF-beta), as well as on recruitment of inflammatory cells in bronchoalveolar lavage (BAL) fluid after aerosol administration of lipopolysaccharide (LPS) in mice. Pretreatment with pirfenidone reduced neutrophil recruitment, TNF-alpha and TGF-beta levels, and MMP-9 secretion. In contrast, pretreatment with batimastat (30 or 60 mg/kg, i.p.) only reduced TNF-alpha and TGF-beta levels. Batimastat did not reduce MMP secretion in BAL fluid but inhibited MMP-9 activity. The increase in tissue inhibitor of matrix metalloproteinase (TIMP)-1 induced by LPS was not modified by the two drugs. These findings demonstrate that the two drugs can inhibit the in vivo increase in MMP induced by LPS, batimastat with a direct inhibitor effect on MMP activity and pirfenidone as a consequence of its antiinflammatory effect.

Enhancement of gelatinase activity during development of subepithelial fibrosis in a murine model of asthma.

Background Chronic asthma is characterized by inflammatory cell infiltration and tissue remodelling leading to subepithelial fibrosis. Metalloproteinases (MMPs) are involved in degradation of extracellular matrix in most chronic inflammatory diseases.

Reduction of matrix metalloproteinase-9 activity by the selective phosphodiesterase 4 inhibitor, RP 73-401 in sensitized mice.

Matrix metalloproteinases are particularly potent in degrading basement membrane collagen and other extracellular matrix components. We have investigated the effects of a selective phosphodiesterase 4 inhibitor, RP 73-401 [N-(3, 5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-methoxybenzamide], on gelatinase (matrix metalloproteinase-2 and matrix metalloproteinase-9) activity in ovalbumin-sensitized and -challenged mice. Twenty-four hours after the last challenge, matrix metalloproteinase activity was evaluated in the bronchoalveolar lavage fluids by a zymography technique, and a significant increase in matrix metalloproteinase-9, but not matrix metalloproteinase-2, activity was noted. When administered orally (0.3-3 mg/kg) 1 h before each ovalbumin challenge, the selective phosphodiesterase 4 inhibitor, RP 73-401, significantly reduced this increased matrix metalloproteinase-9 activity in bronchoalveolar lavage fluids. Our data suggest that RP 73-401 may modulate tissue remodelling associated with lung inflammatory processes including asthma.