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(Chest. 2005;128:3705-3710.)
© 2005 American College of Chest Physicians

L-arginine Attenuates Acute Pulmonary Embolism-Induced Increases in Lung Matrix Metalloproteinase-2 and Matrix Metalloproteinase-9*

Debora C. Souza-Costa, PharmD, MSc; Talita Zerbini; Ana C. Palei; Raquel F. Gerlach, DDS, PhD and Jose E. Tanus-Santos, MD, PhD

* From the Department of Pharmacology (Dr. Souza-Costa, Ms. Zerbini, Ms. Palei, and Dr. Tanus-Santos), Faculty of Medicine of Ribeirao Preto, University of Sao Paulo; and Department of Morphology, Estomatology and Physiology (Dr. Gerlach), Dental School of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, Brazil.

Correspondence to: Jose Eduardo Tanus-Santos, MD, PhD, Assistant Professor, Department of Pharmacology, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo, Av. Bandeirantes, 3900, 14049-900 Ribeirao Preto, SP, Brazil; e-mail: tanus{at}fmrp.usp.br


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objectives: To evaluate the effects of L-arginine on acute pulmonary embolism (APE)-induced pulmonary hypertension and increases in lung matrix metalloproteinase (MMP)-2 and MMP-9 activities.

Design: Prospective trial.

Setting: University laboratory.

Interventions: Using an isolated lung perfusion rat model of APE, we examined whether L-arginine (0, 0.5, 3, and 10 mmol/L; five to seven rats per group) attenuates the pulmonary hypertension induced by the injection of 6.6 mg/kg of 300 µm microspheres into the pulmonary artery. In a second series of experiments (6 to 11 rats per group), we investigated whether nonselective inhibition of nitric oxide (NO) synthases with NG-nitro-L-arginine methyl ester (L-NAME; 4 mmol/L) decreases the effects produced by L-arginine. Lung MMP-2 and MMP-9 activities were determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis gelatin zymography.

Results: L-arginine at 0.5, 3, and 10 mmol/L attenuated APE-induced pulmonary hypertension by 25 to 42% (all p < 0.05). The protective effect of L-arginine was completely reversed by inhibition of NO synthesis with L-NAME. APE was associated with increased lung MMP-2 and MMP-9 activities (both p < 0.05). While L-arginine at 0.5 mmol/L produced no effect on MMPs, L-arginine 3 at mmol/L and 10 mmol/L attenuated the increases in MMP-2 and MMP-9 activities after APE (both p < 0.05).

Conclusions: L-arginine attenuates APE-induced pulmonary hypertension through mechanisms involving increased NO synthesis and maybe attenuation of lung MMP-2 and MMP-9 activities.

Key Words: embolism • L-arginine • matrix metalloproteinases • nitric oxide • pathophysiology • pulmonary hypertension


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Acute pulmonary embolism (APE) is a major cause of morbidity and mortality, and severe APE can lead to death due to the development of acute right heart failure and circulatory shock.1 Three main mechanisms are involved in APE-induced increases in pulmonary vascular resistance: first, the mechanical obstruction of pulmonary vessels plays a major role; second, a neurogenic arteriolar constriction; and third, the release of a variety of vasoconstrictors, especially serotonin, endothelin-1 (ET-1), and thromboxane A2.2345 Although current treatment of APE is focused on removing the mechanical obstruction, studies3678 have addressed the relevance of pulmonary artery vasoconstriction in APE, and the pharmacologic inhibition of the pulmonary vasoconstriction has been suggested as a coadjuvant therapy. Importantly, we have recently found that inhibition of matrix metalloproteinases (MMPs) with doxycycline attenuated the hemodynamic changes in a rat model of APE.9

While MMPs have been classically recognized to play a key role in both physiologic and pathologic degradation of extracellular matrix components, and in the pulmonary vascular remodeling of chronic pulmonary hypertension,10 studies have surprisingly shown that MMPs can modulate vascular reactivity. For example, vascular MMP-211 and neutrophil MMP-912 were shown to cleave big ET-1, releasing the potent vasoconstrictor ET-1 (amino acids 1–32). This is important because ET-1 is a potent vasoconstrictor involved in APE-induced pulmonary hypertension.21314 Moreover, MMP-2 cleavage of vasodilators such as calcitonin gene-related peptide15 and adrenomedullin16 promotes vasoconstriction. Taken together, these previous findings support the idea that MMPs inhibition attenuates the hemodynamic changes observed during APE.9

L-arginine is a substrate for nitric oxide (NO) synthesis and produces pulmonary vasodilatory effects in patients with pulmonary hypertension17 and in hypoxic pulmonary hypertension animal models.18 While we have recently shown that L-arginine has antioxidant effects and attenuates the development of pulmonary hypertension in a rat model of APE,19 it is not known whether treatment with L-arginine is associated with lowered lung MMP-2 and MMP-9 activities after APE. In this study, we hypothesized that L-arginine would attenuate APE-induced pulmonary hypertension and increased lung MMP-2 and MMP-9 levels.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Lung Isolation and Perfusion
The investigation was conducted in accordance with the guidelines of National Research Council. Male Wistar rats (270 to 330 g) were anesthetized with urethane (1 g/kg intraperitoneal). The tracheas were cannulated with polyethylene tubing and connected to an animal ventilator (60 breaths/min). The rats were heparinized (500 U of heparin), and a midsternal thoracotomy was performed as previously described.19 Blood (7 mL) was withdrawn from the right ventricle and mixed with 7 mL of normal saline solution containing 1.5% serum albumin. Although this mixture has lower hematocrit and protein concentration than blood, plasma osmolarity does not change significantly.20 A cannula was inserted into the pulmonary artery via the right ventricle, and a tight ligature was placed around the main trunk of pulmonary artery. The lungs were continuously perfused with a peristaltic pump (Incibras; Sao Paulo, Brazil) at a constant flow rate (9 mL/min), and pulmonary venous outflow was diverted into a reservoir via a cannula that was inserted in the left atrium through the left ventricle and fixed with a ligature at the apex of the heart. Another ligature was placed above the atrioventricular junction to prevent the perfusate mixture from flowing into the ventricles. The perfusate mixture was maintained at 37°C by a heat exchanger. Mean pulmonary arterial pressure (MPAP) was measured from a side arm of the inflow cannula with pressure transducers (COBE; Arvada, CO) zeroed at the level of pulmonary artery cannula. The preparation was allowed to equilibrate for 20 min before the experiments were begun.

Experimental Protocols
In the first series of experiments (five to seven rats per group), we examined the effects of L-arginine on APE-induced pulmonary hypertension and MMP activation. After stabilization,L-arginine (0, 0.5, 3, and 10 mmol/L)19 was added to the perfusate mixture 5 min before lung embolization (or saline solution injection) with 6.6 mg/kg of a suspension of microspheres (Sephadex G50; Pharmacia Biotech; Friburg, Germany)1921 or saline solution injection into the pulmonary artery via a side arm of the inflow cannula.

In the second series of experiments (6 to 11 patients per group), we investigated whether nonselective inhibition of NO synthases with NG-nitro-L-arginine methyl ester (L-NAME) decreases the effects produced by L-arginine. L-NAME at 4 mmol/L or saline solution was added to the to the perfusate mixture 6 min before embolization. L-arginine (3 mmol/L) was then added to the perfusate mixture 5 min before embolization (or saline solution injection). Lung samples were collected at the end of the experiments and stored at – 70°C until used for gelatin zymography of MMP-2 and MMP-9.

Sodium Dodecylsulfate-Polyacrylamide Gel Electrophoresis Gelatin Zymography of MMP-2 and MMP-9
Lung samples were homogenized in buffer containing 20 mmol/L of Tris-HCl, pH 7.4, 1 mmol/L of 1,10-phenanthroline, and 1 mmol/L of phenylmethylsulfonyl fluoride. Briefly, equal volumes (20 µL) of tissue extract normalized for protein concentration were subjected to electrophoresis on 12% sodium dodecylsulfate-polyacrylamide gel electrophoresis co-polymerized with gelatin (1%) as the substrate. After electrophoresis was complete, the gel was incubated for 1 h at room temperature in a 2% Triton X-100 solution, washed two times with water, and incubated at 37°C for 16 h in Tris-HCl buffer, pH 7.4, containing 10 mmol/L of CaCl2. The gels were fixed with 30% methanol and 10% acetic acid, stained with 0.05% Coomassie Brilliant Blue G-250, and then destained with 30% methanol and 10% acetic acid.2223 Gelatinolytic activities were detected as unstained bands against the background of Coomassie blue-stained gelatin. Enzyme activity was assayed by densitometry using a Kodak Electrophoresis Documentation and Analysis System 290 (Kodak; Rochester, NY). The pro and active forms of MMP-2 and MMP-9 were identified as bands at 72 kd and 67 kd, and at 92 kd and 87 kd, respectively.

Statistical Analysis
All the results are expressed as mean = SEM. One-way analysis of variance followed by the Student-Newman-Keuls test was used to compare changes in MPAP and in MMPs activities among groups (StatView for Windows; SAS Institute;, Cary, NC). A probability value < 0.05 was considered the minimum level of statistical significance.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Figure 1 , top, A, shows that L-arginine at 0.5, 3, and 10 mmol/L significantly attenuated APE-induced pulmonary hypertension (all p < 0.05). Interestingly, these three concentrations of L-arginine produced similar reductions in MPAP (from 25 to 42%).



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  		Figure 1.. Top, A: MPAP after saline solution (control, n = 5) or lung embolization (Emb) with 6.6 mg/kg of microspheres after L-arginine at 0, 0.5, 3, and 10 mmol/L was added to the lung perfusate in the Emb (n = 11), L-arginine at 0.5 mmol/L plus Emb (Arg 05 + Emb; n = 6), L-arginine at 3 mmol/L plus Emb (Arg 3 + Emb; n = 6), and L-arginine at 10 mmol/L plus Emb (Arg 10 + Emb; n = 6) groups, respectively. Bottom, B: MPAP after saline solution (control, n = 5), L-arginine at 3 mmol/L (Arg 3, n = 4), L-NAME at 4 mmol/L (n = 4), and after Emb with microspheres with saline solution (Emb, n = 10), Arg 3+ Emb (n = 6), L-NAME at 4 mmol/L (L-NAME + Emb, n = 6), or L-NAME at 4 mmol/L plus L-arginine at 3 mmol/L (L-NAME + Arg 3 + Emb, n = 6) were previously added to the lung perfusate. Results are expressed as mean ± SEM. *p < 0.05 vs Emb group.

 
Figure 1 (bottom, B) shows that that inhibition of NO synthesis with L-NAME produced no significant increases in the severity of APE-induced pulmonary hypertension. Importantly, the protective effect of L-arginine on APE-induced pulmonary hypertension was completely reversed by L-NAME, thus indicating that NO mediates the effects produced by L-arginine.

Figure 2 shows a representative zymogram of lung extract showing activated MMP-9, pro-MMP-2, and activated MMP-2 bands (Fig 2). The pro form of MMP-9, however, was not detected in any gel. Figure 3 shows that lung embolization was associated with increased active MMP-9 and active MMP-2 values compared with control subjects (both p < 0.05). While L-arginine at 0.5 mmol/L produced no effect, treatments with L-arginine at 3 mmol/L and 10 mmol/L were associated with lower MMP-9 and MMP-2 values in the L-arginine at 3 mmol/L plus lung embolization and the L-arginine plus 10 mmol/L plus lung embolization groups, respectively, compared with both lung embolization groups (both p < 0.05; Fig 3, top, A, and center, B). Even though embolization did not significantly enhance pro-MMP-2 values, treatment with L-arginine 10 mmol/L was associated with lower pro-MMP-2 values (p < 0.05; Fig 3, bottom, C).



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  		Figure 2.. Representative zymogram of lung extract showing activated MMP-9, pro-MMP-2, and activated MMP-2 bands. Control animals received only saline solution. L-arginine at 0, 0.5, 3, and 10 mmol/L was added to the lung perfusate in Emb, Arg 0.5 + Emb, Arg 3 + Emb, and Arg 10 + Emb groups, respectively, 5 min before embolization. See Figure 1 legend for expansion of abbreviations.

 


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  		Figure 3.. Lung active MMP-9 (top, A), active MMP-2 (center, B), and pro-MMP-2 (bottom, C) mean values (± SEM). Control animals (n = 5) received only saline solution. L-arginine at 0, 0.5, 3, and 10 mmol/L was added to the lung perfusate in Emb (n = 6), Arg 0.5 + Emb (n = 6), Arg 3 + Emb (n = 6), and Arg 10 + Emb (n = 6) groups, respectively, 5 min before embolization. *p < 0.05 vs Emb group. See Figure 1 legend for expansion of abbreviations.

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The present study shows that APE was associated with significant increases in lung MMP-2 and MMP-9 activities. Treatment with L-arginine attenuated both APE-induced pulmonary hypertension and increased lung MMP-2 and MMP-9 activities.

MMPs are a group of enzymes well known for their involvement in the degradation of many components of the extracellular matrix. However, several MMPs (MMP-1, MMP-2, MMP-3, and MMP-9) are expressed in vascular smooth-muscle cells and in a variety of other cells potentially affecting the pulmonary circulation, including endothelial cells, macrophages, fibroblasts, and alveolar epithelial cells.24

While low levels of MMP activities are usually found in normal lung tissues, increased MMP expression and activities are commonly found during inflammation and lung injury.25 In this regard, the increased lung MMP-2 and MMP-9 activities we have found may reflect the recruitment and migration of inflammatory cells to lung tissues. Importantly, an inflammatory response with an early influx of neutrophils and macrophages within the pulmonary artery wall has been demonstrated in a rat model of APE.26 Therefore, the most likely mechanism underlying the enhanced lung MMP-9 activity we found after APE involves an early APE-induced influx of neutrophils in the pulmonary artery26 and a rapid release of granules containing large amounts of MMP-9.1227 Further supporting this hypothesis, activated neutrophils release superoxide and other reactive oxygen species, which in turn activate MMPs.2728 In addition, other studies2829 have shown that increased mechanical stretch of the vessel wall induces the formation of reactive oxygen species and thereby enhances MMPs release. We1930 and others31 have found increased oxidative stress in rat, dog, and mice models of APE. Because enhanced oxidative stress activates MMP-2 and MMP-9,2728 it is possible that APE-induced oxidative stress after APE may have led to increased lung MMP-2 and MMP-9 activities in the present study.

Similar to our previous results,19 the protective effects of L-arginine were reversed by L-NAME in the present study, therefore implicating increased NO synthesis as a major component of this response. An increased NO production may have protected against oxidative injury through mechanisms involving diminished lipid peroxidation.32 Indeed, we showed that treatment with L-arginine (at concentrations similar to those used in the present study) attenuated APE-induced increase in lipid peroxidation,19 thus suggesting that the protective effects of L-arginine involve antioxidant mechanisms.2223

Consistent with previous results showing thatL-arginine attenuates APE-induced increases in oxidative stress and pulmonary hypertension in rats,19 and that inhibition of MMPs attenuates the hemodynamic changes in a rat model of APE,9 the results of the present study show that L-arginine attenuates both APE-induced pulmonary hypertension and increased lung MMP-2 and MMP-9. Therefore, it is possible the L-arginine may have inhibited APE-induced pulmonary hypertension and increased lung MMP-2 and MMP-9 through antioxidant mechanisms. An attenuated increase in lung MMP-2 and MMP-9 after APE may have led to less pulmonary hypertension. Giving support to this hypothesis, both MMP-211 and MMP-912 have been shown to enhance the release of vasoconstrictors such as ET-1–related peptides, which are potent vasoconstrictors playing a role in APE.21314 Moreover, L-arginine attenuation of APE-induced increases in lung MMP-2 and MMP-9 may have decreased the degradation of vasodilators such as calcitonin gene-related peptide1115 and adrenomedullin,16 thus diminishing vasoconstriction and pulmonary hypertension.

L-arginine produced similar effects to those reported herein during hypoxia-induced pulmonary hypertension in rats, which involves the release of increased amounts of ET-1.18 In addition, a specific MMP inhibitor (batimastat) produced similar beneficial effects in chronically hypoxic rats.33 However, one possible limitation to the use of MMP inhibitors is that combining MMP inhibitors with chemotherapy in humans has been associated with a significant increase in the risk of developing venous thromboembolism.34 Although the mechanisms leading to this effect are not clear at present, the possible therapeutic effects of MMP inhibitors should be examined with caution.

In conclusion, our results demonstrate that L-arginine supplementation leads to negative modulation of lung MMP-2 and MMP-9 activities after APE. The present findings provide new insight into the pathophysiology and treatment of APE-induced pulmonary hypertension. Targeting the NO-cyclic guanosine monophosphate pathway during human APE may prove to be effective in inhibiting the deleterious effects of MMPs activation during APE and maybe the pulmonary vascular remodeling usually found in chronic thromboembolic pulmonary hypertension.


   Footnotes
 
Abbreviations: APE = acute pulmonary embolism; ET = endothelin; L-NAME = NG-nitro-L-arginine methyl ester; MMP = matrix metalloproteinase; MPAP = mean pulmonary artery pressure; NO = nitric oxide

This study was funded by Fundação de Aparo a Pesquisa do Estado de São Paulo (FAPESP-Brazil), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq-Brazil). and Coordenadoria de Aperfeiçoamento de Pessoal de Nível Superior (CAPES-Brazil).

Received for publication December 5, 2004. Accepted for publication May 10, 2005.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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