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(Chest. 2005;128:1069.)
© 2005 American College of Chest Physicians

Protease-Antiprotease Imbalance in Inflammatory Diseases in the Lung

Ken-ichiro Inoue, MD; Hirohisa Takano, MD and Toshikazu Yoshikawa, MD

Graduate School of Medical Science Kyoto Prefectural University of Medicine, Kyoto, Japan, Hiroyuki Sato, Mochida Pharmaceutical Company, Tokyo, Japan

Correspondence to: Ken-ichiro Inoue, MD, Inhalation Toxicology Research Team, and Pathophysiology Research Team, National Institute for Environmental Studies, 16-2 Onogawa, Tsukuba, 305-8506, Japan; e-mail: inoue.kenichirou{at}nies.go.jp

To the Editor:

We are very interested in the extensive research by Vernooy et al,1 who addressed the importance of matrix metalloproteases (MMPs) in the pathogenesis and/or the development of COPD. It is likely to be important to evaluate the activity of the proteases rather than the expression of MMPs. Protease/antiprotease imbalance has also been postulated to be important in the pathogenesis of COPD. However, the authors did not refer to the activity of the inhibitor of MMPs, tissue inhibitor of metalloprotease (TIMP). Thus, evaluation of the activity of TIMP will increase the understanding of the disease.

We are focusing on another protease inhibitor in several inflammatory conditions. Urinary trypsin inhibitor (UTI) is a multivalent Kunitz-type serine protease inhibitor.2 UTI has been widely used as a drug for patients with disseminated intravascular coagulation, shock, and pancreatitis, especially in Japan. UTI can inhibit proteases including trypsin, {alpha}-chymotrypsin, plasmin, cathepsin G, and leukocyte elastase as well as proteases in the coagulation cascade. Also, UTI has been reported to have anti-inflammatory properties in vitro. For instances, UTI inhibits the enhanced production of proinflammatory molecules such as thromboxane B2,3 interleukin-8,4 and tumor necrosis factor-{alpha}5 induced by lipopolysaccharide in vitro. In addition, UTI ameliorates several inflammatory models including ischemia-reperfusion injury,6 hemorrhagic shock,7 septic shock,8 and glomerulonephritis9 in vivo. We have recently exhibited the protective role of UTI in systemic inflammatory model using UTI gene knockout mice.10 The protection was characterized by the inhibition of organ (lung, kidney, and liver) injuries and the enhanced organ expression of proinflammatory cytokines and chemokines.10 More recently, we have demonstrated the protective role of UTI in acute lung injury induced by intratracheal administration of bacterial endotoxin in vivo,11 and have shown that the protection is associated with the inhibition of enhanced lung expression of intercellular adhesion molecule-1.11

Indeed, the amount of UTI in serum reportedly reflects the degree of airway inflammation in children with asthma.12 In conclusion, further investigation targeting protease inhibitors including UTI in inflammatory pulmonary diseases such as COPD may provide novel therapeutic strategies for the diseases.

References

  1. Vernooy, JH, Lindeman, JH, Jacobs, JA, et al (2004) Increased activity of matrix metalloproteinase-8 and matrix metalloproteinase-9 in induced sputum from patients with COPD. Chest 126,1802-1810[Abstract/Free Full Text]
  2. Sato, H, Kajikawa, S, Kuroda, S, et al Impaired fertility in female mice lacking urinary trypsin inhibitor. Biochem Biophys Res Commun 2001;281,1154-1160[CrossRef][ISI][Medline]
  3. Aibiki, M, Cook, JA Ulinastatin, a human trypsin inhibitor, inhibits endotoxin-induced thromboxane B2 production in human monocytes. Crit Care Med 1997;25,430-434[CrossRef][Medline]
  4. Maehara, K, Kanayama, N, Halim, A, et al Down-regulation of interleukin-8 gene expression in HL60 cell line by human Kunitz-type trypsin inhibitor. Biochem Biophys Res Commun 1995;206,927-934[CrossRef][ISI][Medline]
  5. Aosasa, S, Ono, S, Mochizuki, H, et al Mechanism of the inhibitory effect of protease inhibitor on tumor necrosis factor {alpha} production of monocytes. Shock 2001;15,101-105[ISI][Medline]
  6. Yano, T, Anraku, S, Nakayama, R, et al Neuroprotective effect of urinary trypsin inhibitor against focal cerebral ischemia-reperfusion injury in rats. Anesthesiology 2003;98,465-473[CrossRef][Medline]
  7. Masuda, T, Sato, K, Noda, C, et al Protective effect of urinary trypsin inhibitor on myocardial mitochondria during hemorrhagic shock and reperfusion. Crit Care Med 2003;31,1987-1992[CrossRef][Medline]
  8. Tani, T, Aoki, H, Yoshioka, T, et al Treatment of septic shock with a protease inhibitor in a canine model: a prospective, randomized, controlled trial. Crit Care Med 1993;21,925-930[ISI][Medline]
  9. Koizumi, R, Kanai, H, Maezawa, A, et al Therapeutic effects of ulinastatin on experimental crescentic glomerulonephritis in rats. Nephron 2000;84,347-353[CrossRef][Medline]
  10. Inoue, K, Takano, H, Shimada, A, et al Urinary trypsin inhibitor protects against systemic inflammation induced by lipopolysaccharide. Mol Pharmacol 2005;67,673-680[Abstract/Free Full Text]
  11. Inoue, K, Takano, H, Yanagisawa, R, et al Protective role of urinary trypsin inhibitor in acute lung injury induced by lipopolysaccharide. Exp Biol Med (Maywood) 2005;230,281-287[Abstract/Free Full Text]
  12. Yasui, K, Kanda, H, Iwanami, T, et al Increased serum concentration of urinary trypsin inhibitor with asthma exacerbation. Eur Respir J 2003;22,739-742[Abstract/Free Full Text]

J.H.J. Vernooy, PhD

University Hospital Maastricht Maastricht, the Netherlands

Correspondence to: Juanita H.J. Vernooy, PhD, Department of Respiratory Medicine, Nutrition and Toxicology Research Institute (NUTRIM), University Hospital Maastricht, PO Box 5800, NL-6202 AZ Maastricht, the Netherlands; email: j.vernooy{at}pul.unimaas.nl

To the Editor:

We appreciate the interest of Dr. Inoue and his group in our work. We fully endorse the importance of studying the protease/antiprotease balance rather than the expression of proteases. We therefore applied specific immunocapture activity assays that measure any active matrix metalloproteinase (MMP) but are insensitive to MMP-inhibitor complexes (such as MMP-tissue inhibitor of metalloproteinase or MMP-{alpha}2M complexes). Our finding of active MMPs in sputum is therefore indicative of a protease-antiprotease imbalance in COPD patients. The possible involvement of urinary trypsin inhibitor (UTI) is interesting, and the role of UTIs in COPD merits further study. Yet UTI (a serine protease inhibitor) does not inhibit MMP activity and will thus not influence the MMP-anti protease balance.





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