**11. References**


Diverse Activities for Proteinases in the

*Biol.* 34: 1-5.

*Health* 11: 50-58.

167: 1083-1089.

L420-L427.

Pathogenesis of Chronic Obstructive Pulmonary Disease 61

[27] Black, R. A. 2002. Tumor necrosis factor-alpha converting enzyme. *Int. J. Biochem. Cell* 

[28] Murphy, G., and A. J. P. Docherty. 1992. The matrix metalloproteinases and their

[29] Woessner, J. F., Jr. 1991. Matrix metalloproteinases and their inhibitors in connective

[31] Amour, A., P. M. Slocombe, A. Webster, M. Butler, C. G. Knight, B. J. Smith, P. E.

[33] Larsson, C. 1978. Natural history and life expectancy in severe alpha 1-antitrypsin

[34] Gross, P., E. A. Pfitzer, E. Tolker, M. A. Babyak, and M. Kaschak. 1965. Experimental

[35] Hubbard, R. C., G. Fells, J. Gadek, S. Pacholok, J. Humes, and R. G. Crystal. 1991.

[38] Balbin, M., A. Fueyo, A. M. Tester, A. M. Pendas, A. S. Pitiot, A. Astudillo, C. M.

increased skin tumor susceptibility to male mice. *Nat. Genet.* 35: 252-257. [39] Churg, A., R. D. Wang, H. Tai, X. Wang, C. Xie, J. Dai, S. D. Shapiro, and J. L. Wright.

[40] Senior, R. M., G. L. Griffin, and R. P. Mecham. 1980. Chemotactic activity of elastin-

[41] Hunninghake, G. W., J. M. Davidson, S. Rennard, S. Szapiel, J. E. Gadek, and R. G.

[42] Shao, M. X., T. Nakanaga, and J. A. Nadel. 2004. Cigarette smoke induces MUC5AC

[43] Kohri, K., I. F. Ueki, and J. A. Nadel. 2002. Neutrophil elastase induces mucin

Stephens, C. Shelley, M. Hutton, V. Knauper, A. J. Docherty, and G. Murphy. 1998. TNF-alpha converting enzyme (TACE) is inhibited by TIMP-3. *FEBS Lett.* 435: 39-44. [32] Henskens, Y. M. C., E. C. I. Veerman, and A. V. N. Nieuw Amerongen. 1996. Cystatins

emphysema. Its production with papain in normal and silicotic rats. *Arch. Environ.* 

Neutrophil accumulation in the lung in 1-antitrypsin deficiency. Spontaneous release of leukotriene B4 by alveolar macrophages. *J. Clin. Invest.* 88: 891-897. [36] Bedard, M., C. D. McClure, N. L. Schiller, C. Francoeur, A. Cantin, and M. Denis. 1993.

Release of interleukin-8, interleukin-6, and colony-stimulating factors by upper airway epithelial cells: Implications for cystic fibrosis. *Am. J. Respir. Cell Mol. Biol.* 9: 455-462. [37] Van Den Steen, P. E., P. Proost, A. Wuyts, J. Van Damme, and G. Opdenakker. 2000.

Neutrophil gelatinase B potentiates interleukin-8 tenfold by aminoterminal processing, whereas it degrades CTAP-III, PF-4, and GRO- and leaves RANTES

Overall, S. D. Shapiro, and C. Lopez-Otin. 2003. Loss of collagenase-2 confers

2003. Macrophage metalloelastase mediates acute cigarette smoke-induced inflammation via tumor necrosis factor-alpha release. *Am. J. Respir. Crit Care Med.*

Crystal. 1981. Elastin fragments attract macrophage precursors to diseased sites in

mucin overproduction via tumor necrosis factor-alpha-converting enzyme in human airway epithelial (NCI-H292) cells. *Am. J. Physiol Lung Cell Mol. Physiol* 287:

production by ligand-dependent epidermal growth factor receptor activation. *Am.* 

necrosis factor- from cells. *Nature* 385: 729-733.

inhibitors. *Am. J. Respir. Cell Mol. Biol.* 7: 120-125.

[30] Black, R. A. 2004. TIMP3 checks inflammation. *Nat. Genet.* 36: 934-935.

in health and disease. *Biol. Chem. Hoppe-Seyler* 377: 71-86.

deficiency, Pi Z. *Acta Med. Scand.* 204: 345-351.

and MCP-2 intact. *Blood* 96: 2673-2681.

derived peptides. *J Clin. Invest* 66: 859-862.

pulmonary emphysema. *Science* 212: 925-927.

*J. Physiol Lung Cell Mol. Physiol* 283: L531-L540.

tissue remodeling. *FASEB J.* 5: 2145-2154.

and D. P. Cerretti. 1997. A metalloproteinase disintegrin that releases tumour-


[11] Taipale, J., K. Koli, and J. Keski-Oja. 1992. Release of transforming growth factor-beta 1

[12] Saksela, O., and D. B. Rifkin. 1988. Cell-associated plasminogen activation: Regulation

[13] Raza, S. L., L. C. Nehring, S. D. Shapiro, and L. A. Cornelius. 2000. Proteinase activated

[14] Churg, A., X. Wang, R. D. Wang, S. C. Meixner, E. L. Pryzdial, and J. L. Wright. 2007.

[16] Carrell, R. W. 1986. Alpha1-antitrypsin: Molecular pathology, leukocytes, and tissue

[17] Fu, X., S. Y. Kassim, W. C. Parks, and J. W. Heinecke. 2001. Hypochlorous acid

[18] Murphy, G., H. Stanton, S. Cowell, G. Butler, V. Knauper, S. Atkinson, and J. Gavrilovic. 1999. Mechanisms for pro matrix metalloproteinase activation. *APMIS* 107: 38-44. [19] Cao, J., A. Rehemtulla, M. Pavlaki, P. Kozarekar, and C. Chiarelli. 2005. Furin directly

[20] Imai, K., E. Ohuchi, T. Aoki, H. Nomura, Y. Fujii, H. Sato, M. Seiki, and Y. Okada. 1996.

[21] Shapiro, S. D., E. J. Campbell, R. M. Senior, and H. G. Welgus. 1991. Proteinases secreted by human mononuclear phagocytes. *J. Rheumatol.* 27: 95-98. [22] Rajavashisth, T. B., X. P. Xu, S. Jovinge, S. Meisel, X. O. Xu, N. N. Chai, M. C. Fishbein,

[24] Takino, T. H., H. Sato, A. Shinagawa, and M. Seiki. 1995. Identification of the second

[25] Primakoff, P., and D. G. Myles. 2000. The ADAM gene family: surface proteins with

[26] Black, R. A., C. T. Rauch, C. J. Kozlosky, J. J. Peschon, J. L. Slack, M. F. Wolfson, B. J.

activation by proinflammatory mediators. *Circulation* 99: 3103-3109. [23] Sato, H., T. Takino, Y. Okada, J. Cao, A. Shinagawa, E. Yamamoto, and M. Seiki. 1994. A

smoke-stimulated macrophages. *Am. J Respir. Cell Mol. Biol* 37: 144-151. [15] Smyth, M. J., M. D. O'Connor, and J. A. Trapani. 1996. Granzymes: a variety of serine

plasmin and thrombin. *J Biol Chem.* 267: 25378-25384.

*Chem.* 52: 41243-41250.

damage. *J. Clin. Invest.* 78: 1427-1431.

myeloperoxidase. *J Biol Chem.* 276: 41279-41287.

proteinase. *J Biol Chem.* 280: 10974-10980.

MMP family. *J. Biol. Chem.* 270: 23013-23020.

adhesion and protease activity. *Trends Genet.* 16: 83-87.

555-562.

2707-2710.

370: 61-65.

and physiological functions. *Ann. Rev. Cell Biol.* 4: 93-126.

from the pericellular matrix of cultured fibroblasts and fibrosarcoma cells by

receptor-1 regulation of macrophage elastase secretion by serine proteinases. *J. Biol.* 

Alpha1-antitrypsin suppresses TNF-alpha and MMP-12 production by cigarette

protease specificities encoded by genetically distinct subfamilies. *J Leukoc. Biol* 60:

oxygenates the cysteine switch domain of pro-matrilysin (MMP-7). A mechanism for matrix metalloproteinase activation and atherosclerotic plaque rupture by

cleaves proMMP-2 in the trans-Golgi network resulting in a nonfunctioning

Membrane-type matrix metalloproteinase 1 is a gelatinolytic enzyme and is secreted in a complex with tissue inhibitor of metalloproteinases 2. *Cancer Res.* 56:

S. Kaul, B. Cercek, B. Sharifi, and P. K. Shah. 1999. Membrane type 1 matrix metalloproteinase expression in human atherosclerotic plaques: evidence for

matrix metalloproteinase expressed on the surface of invasive tumour cells. *Nature*

membrane-type matrix metalloproteinase (MT-MMP-2) gene from a human placenta cDNA library. MT-MMPs form a unique membrane-type subclass in the

Castner, K. L. Stocking, P. Reddy, S. Srinivasan, N. Nelson, N. Boiani, K. A. Schooley, M. Gerhart, R. Davis, J. N. Fitzner, R. S. Johnson, R. J. Paxton, C. J. March, and D. P. Cerretti. 1997. A metalloproteinase disintegrin that releases tumournecrosis factor- from cells. *Nature* 385: 729-733.


Diverse Activities for Proteinases in the

Suppl: 69-74.

123: 259-267.

368-374.

*Physiol* 66: 2109-2116.

*Engl. J Med* 361: 2599-2608.

168: 199-207.

*Med.* 160: 893-898.

and healthy subjects. *Respir. Med.* 97: 634-639.

Pathogenesis of Chronic Obstructive Pulmonary Disease 63

[59] Betsuyaku, T., M. Nishimura, K. Takeyabu, M. Tanino, K. Miyamoto, and Y. Kawakami.

neutrophil elastase in bronchoalveolar lavage fluid. *Respiration* 67: 261-267. [60] Betsuyaku, T., M. Nishimura, A. Yoshioka, K. Takeyabu, K. Miyamoto, and Y.

[61] Cataldo, D., C. Munaut, A. Noel, F. Frankenne, P. Bartsch, J. M. Foidart, and R. Louis.

[62] Hill, A. T., D. Bayley, and R. A. Stockley. 1999. The interrelationship of sputum

[63] Beeh, K. M., J. Beier, O. Kornmann, and R. Buhl. 2003. Sputum matrix

[64] Imai, K., S. S. Dalal, E. S. Chen, R. Downey, L. L. Schulman, M. Ginsburg, and J.

cigarette smoking and obstruction of airflow. *J Korean Med. Sci.* 18: 821-827. [66] Ning, W., Y. Dong, J. Sun, C. Li, M. A. Matthay, C. A. Feghali-Bostwick, and A. M. Choi.

[67] Hodge, S., G. Hodge, J. Nairn, M. Holmes, and P. N. Reynolds. 2006. Increased airway

[68] Churg, A., K. Zay, S. Shay, C. Xie, S. D. Shapiro, R. Hendricks, and J. L. Wright. 2002.

[69] Li, X. Y., I. Rahman, K. Donaldson, and W. MacNee. 1996. Mechanisms of cigarette smoke induced increased airspace permeability. *Thorax* 51: 465-471. [70] Burns, A. R., S. P. Hosford, L. A. Dunn, D. C. Walker, and J. C. Hogg. 1989. Respiratory

[71] Churg, A., R. D. Wang, C. Xie, and J. L. Wright. 2003. alpha-1-Antitrypsin ameliorates

[72] Hunninghake, G. M., M. H. Cho, Y. Tesfaigzi, M. E. Soto-Quiros, L. Avila, J. Lasky-Su,

human lung fibroblasts. *Am. J Respir. Cell Mol. Biol* 36: 480-490.

2000. Decline in FEV(1) in community-based older volunteers with higher levels of

Kawakami. 1996. [Neutrophil elastase and elastin-derived peptides in BAL fluid and emphysematous changes on CT scans]. *Nihon Kyobu Shikkan Gakkai Zasshi* 34

2000. MMP-2- and MMP-9-linked gelatinolytic activity in the sputum from patients with asthma and chronic obstructive pulmonary disease. *Int. Arch. Allergy Immunol.*

inflammatory markers in patients with chronic bronchitis. *Am. J. Respir. Crit Care* 

metalloproteinase-9, tissue inhibitor of metalloprotinease-1, and their molar ratio in patients with chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis

D'Armiento. 2001. Human collagenase (matrix metalloproteinase-1) expression in the lungs of patients with emphysema. *Am. J. Respir. Crit Care Med.* 163: 786-791. [65] Kang, M. J., Y. M. Oh, J. C. Lee, D. G. Kim, M. J. Park, M. G. Lee, I. G. Hyun, S. K. Han,

Y. S. Shim, and K. S. Jung. 2003. Lung matrix metalloproteinase-9 correlates with

2007. Cigarette smoke stimulates matrix metalloproteinase-2 activity via EGR-1 in

granzyme b and perforin in current and ex-smoking COPD subjects. *COPD.* 3: 179-187.

Acute cigarette smoke-induced connective tissue breakdown requires both neutrophils and macrophage metalloelastase in mice. *Am. J. Respir. Cell Mol. Biol* 27:

epithelial permeability after cigarette smoke exposure in guinea pigs. *J. Appl.* 

cigarette smoke-induced emphysema in the mouse. *Am. J. Respir. Crit Care Med.*

C. Stidley, E. Melen, C. Soderhall, J. Hallberg, I. Kull, J. Kere, M. Svartengren, G. Pershagen, M. Wickman, C. Lange, D. L. Demeo, C. P. Hersh, B. J. Klanderman, B. A. Raby, D. Sparrow, S. D. Shapiro, E. K. Silverman, A. A. Litonjua, S. T. Weiss, and J. C. Celedon. 2009. MMP12, lung function, and COPD in high-risk populations. *N.* 


[44] Deshmukh, H. S., L. M. Case, S. C. Wesselkamper, M. T. Borchers, L. D. Martin, H. G.

[45] Sommerhoff, C. P., J. A. Nadel, C. B. Basbaum, and G. H. Caughey. 1990. Neutrophil

[46] Casalino-Matsuda, S. M., M. E. Monzon, and R. M. Forteza. 2006. Epidermal growth factor

[49] Yu, Q., and I. Stamenkovic. 2000. Cell surface-localized matrix metalloproteinase-9

[50] Chua, F., S. E. Dunsmore, P. H. Clingen, S. E. Mutsaers, S. D. Shapiro, A. W. Segal, J.

[51] Mohan, S., G. R. Thompson, Y. G. Amaar, G. Hathaway, H. Tschesche, and D. J.

produced and secreted by human osteoblasts. *Biochemistry* 41: 15394-15403. [52] Fowlkes, J. L., D. M. Serra, H. Nagase, and K. M. Thrailkill. 1999. MMPs are IGFBP-

[53] Damiano, V. V., A. Tsang, U. Kucich, W. R. Abrams, J. Rosenbloom, P. Kimbel, and G.

[54] Morrison, H. M., H. G. Welgus, C. A. Owen, R. A. Stockley, and E. J. Campbell. 1999.

[55] Reilly, J. J., and H. A. Chapman, Jr. 1988. Association between alveolar macrophage

[56] Finlay, G. A., L. O'Driscoll, K. J. Russell, E. M. D'Arcy, J. B. l. Masterson, M. X.

[57] Abboud, R. T., A. F. Ofulue, R. H. Sansores, and N. L. Muller. 1998. Relationship of

[58] Betsuyaku, T., M. Nishimura, K. Takeyabu, M. Tanino, P. Venge, S. Xu, and Y.

bleomycin-induced pulmonary fibrosis. *Am. J Pathol.* 170: 65-74.

*Care Med.* 171: 305-314.

*Thorax* 39: 663-667.

*Genes Dev.* 14: 163-176.

*N. Y. Acad. Sci.* 878: 696-699.

*J. Clin. Invest.* 78: 482-493.

156: 240-247.

analyses. *Biochim. Biophys. Acta* 1430: 179-190.

smokers. *Am. Rev. Respir. Dis.* 138: 1422-1428.

and CT evidence of emphysema. *Chest* 113: 1257-1263.

serous cells. *J. Clin. Invest.* 85: 862-869.

Shertzer, J. A. Nadel, and G. D. Leikauf. 2005. Metalloproteinases mediate mucin 5AC expression by epidermal growth factor receptor activation. *Am. J Respir. Crit* 

elastase and cathespin G stimulate secretion from cultured bovine airway gland

receptor activation by epidermal growth factor mediates oxidant-induced goblet cell metaplasia in human airway epithelium. *Am. J. Respir. Cell Mol. Biol.* 34: 581-591. [47] Amitani, R., R. Wilson, A. Rutmen, R. Reid, C. Ward, D. Burnett, R. A. Stockley, and P.

J. Cole. 1991. Effects of human neutrophil elastase and *Pseudomonas aeruginosa* proteinases on human respiratory epithelium. *Am. J. Respir. Cell Mol. Biol.* 4: 26-32. [48] Smallman, L. A., S. L. Hill, and R. A. Stockley. 1984. Reduction of ciliary beat frequency

*in vitro* by sputum from patients with bronchiectasis: A serine proteinase effect.

proteolytically activates TGF-beta and promotes tumor invasion and angiogenesis.

Roes, and G. J. Laurent. 2007. Mice lacking neutrophil elastase are resistant to

Baylink. 2002. ADAM-9 is an insulin-like growth factor binding protein-5 protease

degrading proteinases: implications for cell proliferation and tissue growth. *Ann.* 

Weinbaum. 1986. Immunolocalization of elastase in human emphysematous lungs.

Interaction between leukocyte elastase and elastin: quantitative and catalytic

plasminogen activator activity and indices of lung function in young cigarette

Fitzgerald, and C. M. O'Connor. 1997. Matrix metalloproteinase expression and production by alveolar macrophages in emphysema. *Am. J. Respir. Crit. Care Med.*

alveolar macrophage plasminogen activator and elastase activities to lung function

Kawakami. 1999. Neutrophil granule proteins in bronchoalveolar lavage fluid from subjects with subclinical emphysema. *Am. J. Respir. Crit. Care Med.* 159: 1985-1991.


Diverse Activities for Proteinases in the

447-454.

L1401.

*Med.* 173: 623-631.

278: 28403-28409.

278: 28403-28409.

*Biol. Chem.* 267: 5005-5012.

*Biol Chem.* 280: 30201-30205.

*Respir. Crit Care Med.* 163: 737-744.

Pathogenesis of Chronic Obstructive Pulmonary Disease 65

[87] Kasahara, Y., R. M. Tuder, C. D. Cool, D. A. Lynch, S. C. Flores, and N. F. Voelkel. 2001.

[88] Aoshiba, K., N. Yokohori, and A. Nagai. 2003. Alveolar wall apoptosis causes lung destruction and emphysematous changes. *Am. J Respir. Cell Mol. Biol* 28: 555-562. [89] Hodge, S., G. Hodge, M. Holmes, and P. N. Reynolds. 2005. Increased airway epithelial

[90] Aoshiba, K., J. Tamaoki, and A. Nagai. 2001. Acute cigarette smoke exposure induces

[91] Kasahara, Y., R. M. Tuder, L. Taraseviciene-Stewart, T. D. Le Cras, S. Abman, P. K.

[92] Owen, C. A. 2005. Proteinases and oxidants as targets in the treatment of chronic

[93] Foronjy, R. F., O. Mirochnitchenko, O. Propokenko, V. Lemaitre, Y. Jia, M. Inouye, Y.

[94] Kassim, S. Y., X. Fu, W. C. Liles, S. D. Shapiro, W. C. Parks, and J. W. Heinecke. 2005.

[95] Fu, X., S. Y. Kassim, W. C. Parks, and J. W. Heinecke. 2003. Hypochlorous acid

[96] Fu, X., S. Y. Kassim, W. C. Parks, and J. W. Heinecke. 2003. Hypochlorous acid

[97] Rahman, I., and W. MacNee. 1996. Role of oxidants/antioxidants in smoking-induced

[98] Sires, U. I., G. Murphy, H. G. Welgus, and R. M. Senior. 1994. Matrilysin is much more

[99] Desrochers, P. E., J. J. Jeffrey, and S. J. Weiss. 1991. Interstitial collagenase (matrix metalloproteinase-1) expresses serpinase activity. *J. Clin. Invest.* 87: 2258-2265. [100] Desrochers, P. E., K. Mookhtiar, H. E. Van Wart, K. A. Hasty, and S. J. Weiss. 1992.

[101] Desrochers, P. E., and S. J. Weiss. 1988. Proteolytic inactivation of alpha-1-proteinase inhibitor by a neutrophil metalloproteinase. *J. Clin. Invest.* 81: 1646-1650.

lung diseases. *Free Radic. Biol Med.* 21: 669-681.

antitrypsin. *Biochem. Biophys. Res. Commun.* 204: 613-620.

lung cell apoptosis and emphysema. *J. Clin. Invest* 106: 1311-1319.

obstructive pulmonary disease. *Proc. Am. Thorac. Soc.* 2: 373-385.

Endothelial cell death and decreased expression of vascular endothelial growth factor and vascular endothelial growth factor receptor 2 in emphysema. *Am. J.* 

and T-cell apoptosis in COPD remains despite smoking cessation. *Eur. Respir. J* 25:

apoptosis of alveolar macrophages. *Am. J Physiol Lung Cell Mol. Physiol* 281: L1392-

Hirth, J. Waltenberger, and N. F. Voelkel. 2000. Inhibition of VEGF receptors causes

Okada, and J. M. D'Armiento. 2006. Superoxide dismutase expression attenuates cigarette smoke- or elastase-generated emphysema in mice. *Am. J. Respir. Crit Care* 

NADPH oxidase restrains the matrix metalloproteinase activity of macrophages. *J* 

generated by myeloperoxidase modifies adjacent tryptophan and glycine residues in the catalytic domain of matrix metalloproteinase-7 (matrilysin): an oxidative mechanism for restraining proteolytic activity during inflammation. *J. Biol Chem.*

generated by myeloperoxidase modifies adjacent tryptophan and glycine residues in the catalytic domain of matrix metalloproteinase-7 (matrilysin): an oxidative mechanism for restraining proteolytic activity during inflammation. *J Biol Chem.*

efficient than other metalloproteinases in the proteolytic inactivation of alpha 1-

Proteolytic inactivation of alpha 1-proteinase inhibitor and alpha 1 antichymotrypsin by oxidatively activated human neutrophil metalloproteinases. *J.* 


[73] Hautamaki, R. D., D. K. Kobayashi, R. M. Senior, and S. D. Shapiro. 1997. Requirement

[74] Martin, R. L., S. D. Shapiro, S. E. Tong, and H. van Wart. 2001. Macrophage

[75] Houghton, A. M., P. A. Quintero, D. L. Perkins, D. K. Kobayashi, D. G. Kelley, L. A.

[76] Maeno, T., A. M. Houghton, P. A. Quintero, S. Grumelli, C. A. Owen, and S. D. Shapiro.

[77] Grumelli, S., D. B. Corry, L. Z. Song, L. Song, L. Green, J. Huh, J. Hacken, R. Espada, R.

[78] Shapiro, S. D., N. M. Goldstein, A. M. Houghton, D. K. Kobayashi, D. Kelley, and A.

[79] Churg, A., H. Tai, T. Coulthard, R. Wang, and J. L. Wright. 2006. Cigarette smoke drives

[80] Churg, A., R. Wang, X. Wang, P. O. Onnervik, K. Thim, and J. L. Wright. 2007. Effect of

[81] D'Armiento, J., S. S. Dalal, Y. Okada, R. A. Berg, and K. Chada. 1992. Collagenase

[82] Wang, Z., T. Zheng, Z. Zhu, R. J. Homer, R. J. Riese, H. A. Chapman, Jr., S. D. Shapiro,

[83] Zheng, T., Z. Zhu, Z. Wang, R. J. Homer, B. Ma, R. J. Riese, Jr., H. A. Chapman, Jr., S. D.

[84] Kang, M. J., R. J. Homer, A. Gallo, C. G. Lee, K. A. Crothers, S. J. Cho, C. Rochester, H.

pulmonary emphysema and inflammation. *J. Immunol.* 178: 1948-1959. [85] Lanone, S., T. Zheng, Z. Zhu, W. Liu, C. G. Lee, B. Ma, Q. Chen, R. J. Homer, J. Wang, L.

smoke-induced emphysema in mice. *J. Immunol.* 178: 8090-8096.

Hansel, ed. Prog. Respir. Res. Basel Karger. 177-180.

emphysema in mice. *Am. J. Pathol.* 163: 2329-2335.

remodelling in guinea pigs. *Thorax* 62: 706-713.

adult murine lung. *J Exp. Med.* 192: 1587-1600.

pulmonary emphysema. *J Immunol* 174: 8106-8115.

277: 2002-2004.

955-961.

1081-1093.

emphysema. *PLoS. Med.* 1: e8.

*Respir. Crit Care Med.* 174: 1327-1334.

for macrophage elastase for cigarette smoke-induced emphysema in mice. *Science*

Metalloelastase Inhibitors. In *New Drugs for Asthma, Allergy and COPD*. T. B. P.

Marconcini, R. P. Mecham, R. M. Senior, and S. D. Shapiro. 2006. Elastin fragments drive disease progression in a murine model of emphysema. *J Clin. Invest* 116: 753-759.

2007. CD8+ T Cells are required for inflammation and destruction in cigarette

Bag, D. E. Lewis, and F. Kheradmand. 2004. An immune basis for lung parenchymal destruction in chronic obstructive pulmonary disease and

Belaaouaj. 2003. Neutrophil elastase contributes to cigarette smoke-induced

small airway remodeling by induction of growth factors in the airway wall. *Am. J.* 

an MMP-9/MMP-12 inhibitor on smoke-induced emphysema and airway

expression in the lungs of transgenic mice causes pulmonary emphysema. *Cell* 71:

and J. A. Elias. 2000. Interferon gamma induction of pulmonary emphysema in the

Shapiro, and J. A. Elias. 2000. Inducible targeting of IL-13 to the adult lung causes matrix metalloproteinase- and cathepsin-dependent emphysema. *J. Clin. Invest* 106:

Cain, G. Chupp, H. J. Yoon, and J. A. Elias. 2007. IL-18 is induced and IL-18 receptor alpha plays a critical role in the pathogenesis of cigarette smoke-induced

A. Rabach, M. E. Rabach, J. M. Shipley, S. D. Shapiro, R. M. Senior, and J. A. Elias. 2002. Overlapping and enzyme-specific contributions of matrix metalloproteinases-9 and -12 in IL-13-induced inflammation and remodeling. *J. Clin. Invest* 110: 463-474. [86] Zheng, T., M. J. Kang, K. Crothers, Z. Zhu, W. Liu, C. G. Lee, L. A. Rabach, H. A.

Chapman, R. J. Homer, D. Aldous, G. T. De Sanctis, S. Underwood, M. Graupe, R. A. Flavell, J. A. Schmidt, and J. A. Elias. 2005. Role of cathepsin S-dependent epithelial cell apoptosis in IFN-gamma-induced alveolar remodeling and


Diverse Activities for Proteinases in the

106: 667-676.

*Lett.* 421: 159-164.

7791-7803.

specificity. *J. Biol. Chem.* 267: 9612-9618.

serine proteinases. *J. Cell Biol.* 131: 775-789.

Pathogenesis of Chronic Obstructive Pulmonary Disease 67

[118] Murphy, G., J. A. Allan, F. Willenbrock, M. I. Cockett, J. P. O'Connell, and A. J. P.

[119] Campbell, E. J., and M. A. Campbell. 1988. Pericellular proteolysis by neutrophils in

[120] Wright, S. D., and S. C. Silverstein. 1984. Phagocytosing macrophages exclude proteins

[121] D'Ortho, M. P., H. Stanton, M. Butler, S. J. Atkinson, G. Murphy, and R. M. Hembry.

[122] Owen, C. A., M. A. Campbell, P. L. Sannes, S. S. Boukedes, and E. J. Campbell. 1995.

[123] Campbell, E. J., M. A. Campbell, and C. A. Owen. 2000. Bioactive proteinase 3 on the

[124] Owen, C. A., and E. J. Campbell. 1998. Angiotensin II generation at the cell surface of

[125] Owen, C. A., M. A. Campbell, S. S. Boukedes, and E. J. Campbell. 1995. Inducible binding

extracellular proteolytic activity of cathepsin G. *J. Immunol.* 155: 5803-5810. [126] Owen, C. A., Z. Hu, B. Barrick, and S. D. Shapiro. 2003. Inducible expression of tissue

[127] Owen, C. A., Z. Hu, C. Lopez-Otin, and S. D. Shapiro. 2004. Membrane-bound matrix

[128] Takeyama, K., C. Agusti, I. Ueki, J. Lausier, L. O. Cardell, and J. A. Nadel. 1998.

[129] Burnett, D., S. C. Afford, E. J. Campbell, R. A. Rios-Mollineda, and R. A. Stockley. 1987.

[130] Yoshioka, A., T. Betsuyaku, M. Nishimura, K. Miyamoto, T. Kondo, and Y. Kawakami.

[131] Hodge, S., G. Hodge, J. Ahern, H. Jersmann, M. Holmes, and P. N. Reynolds. 2007.

[132] Vandivier, R. W., V. A. Fadok, P. R. Hoffmann, D. L. Bratton, C. Penvari, K. K. Brown,

[133] Naylor, E. J., D. Bakstad, M. Biffen, B. Thong, P. Calverley, S. Scott, C. A. Hart, R. J.

surface of neutrophils. *Am. J. Resp. Cell Mol. Biol* 29: 283-294.

and adhesion molecules. *Am. J. Physiol* 275: L294-L302.

emphysema. *Am. J Respir. Crit Care Med.* 152: 2127-2132.

Implications in COPD. *Am. J Respir. Cell Mol. Biol*.

fibrosis and bronchiectasis. *J Clin. Invest* 109: 661-670.

from zones of contact with targets. *Nature* 309: 359-361.

susceptibility to inhibition. *J. Immunol.* 165: 3366-3374.

resistant to inhibition. *J. Immunol.* 160: 1436-1443.

Docherty. 1992. The role of the C-terminal domain in collagenase and stromelysin

the presence of proteinase inhibitors: Effects of substrate opsonization. *J. Cell Biol.*

1998. MT1-MMP on the cell surface causes focal degradation of gelatin films. *FEBS* 

Cell-surface-bound elastase and cathepsin G on human neutrophils. A novel, nonoxidative mechanism by which neutrophils focus and preserve catalytic activity of

cell surface of human neutrophils: quantification, catalytic activity, and

activated neutrophils: Novel cathepsin G-mediated catalytic activity that is

of cathepsin G to the cell surface of neutrophils: A mechanism for mediating

inhibitor of metalloproteinases-resistant matrix metalloproteinase-9 on the cell

metalloproteinase-8 on activated polymorphonuclear cells is a potent, tissue inhibitor of metalloproteinase-resistant collagenase and serpinase. *J. Immunol.* 172:

Neutrophil-dependent goblet cell degranulation: role of membrane-bound elastase

Characterization of elastase activity in bronchoalveolar lavage samples., 135 ed. A507.

1995. Excessive neutrophil elastase in bronchoalveolar lavage fluid in subclinical

Smoking Alters Alveolar Macrophage Recognition and Phagocytic Ability:

J. D. Brain, F. J. Accurso, and P. M. Henson. 2002. Elastase-mediated phosphatidylserine receptor cleavage impairs apoptotic cell clearance in cystic

Moots, and S. W. Edwards. 2007. Haemophilus influenzae induces neutrophil


[102] Gronski, T. J., Jr., R. L. Martin, D. K. Kobayashi, B. C. Walsh, M. C. Holman, M. Huber,

[103] Cantin, A., G. Bilodeau, and R. Begin. 1989. Granulocyte elastase-mediated proteolysis

[104] Wu, K., T. Urano, H. Ihara, Y. Takada, M. Fujie, M. Shikimori, K. Hashimoto, and A.

[105] Johnson, D., and J. Travis. 1977. Inactivation of human 1 proteinase inhibitor by thiol

[106] Sponer, M., H.-P. Nick, and H.-P. Schnebli. 1991. Different susceptibility of elastase

[107] Okada, Y., S. Watanabe, I. Nakanishi, J. Kishi, T. Hayakawa, W. Watorek, J. Travis, and

[110] Carp, H., and A. Janoff. 1980. Potential mediator of inflammation: Phagocyte-derived

[111] Reddy, V. Y., P. E. Desrochers, S. V. Pizzo, S. L. Gonias, J. A. Sahakian, R. L. Levine,

[112] Abboud, R. T., T. Fera, A. Richter, M. Z. Tabona, and S. Johal. 1985. Acute effect of

[113] Gadek, J. E., G. A. Fells, and R. G. Crystal. 1979. Cigarette smoking induces functional

[114] Stone, P. J., J. D. Calore, S. E. McGowan, J. Bernardo, G. L. Snider, and C. Franzblau.

[115] Morrison, H. M., H. G. Welgus, R. A. Stockley, D. Burnett, and E. J. Campbell. 1990.

elastin-bound elastase by bronchial inhibitor. *Biochem. J.* 238: 269-273. [117] Allan, J. A., A. J. P. Docherty, P. J. Barker, N. S. Huskisson, J. J. Reynolds, and G.

tetramers into dysfunctional dimers. *J. Biol. Chem.* 269: 4683-4691.

cigarette smokers is not decreased. *Science* 221: 1187-1189.

neutrophil elastase and other serine proteinases. *FEBS-Lett.* 229: 157-160. [108] Carp, H., and A. Janoff. 1980. Inactivation of bronchial mucous proteinase inhibitor by cigarette smoke and phagocyte-derived oxidants. *Exp. Lung Res.* 1: 225-237. [109] Carp, H., and A. Janoff. 1979. In vitro suppression of serum elastase-inhibitory capacity

*Pseudomonas aeruginosa*. *Biol. Chem. Hoppe-Seyler* 372: 963-970.

12189-12194.

*Pulmonol.* 7: 12-17.

fibrinolysis. *Blood* 86: 1056-1061.

proteinases. *Biochem. J.* 163: 639-641.

leukocytes. *J. Clin. Invest.* 63: 793-797.

lavage fluid. *Am. Rev. Respir. Dis.* 131: 79-85.

components. *Biochem. J.* 309: 299-306.

vitro. *J. Clin. Invest.* 66: 987-995.

H. E. Van Wart, and S. D. Shapiro. 1997. Hydrolysis of a broad spectrum of extracellular matrix proteins by human macrophage elastase. *J. Biol. Chem.* 272:

of alpha1-antitrypsin in cystic fibrosis bronchopulmonary secretions. *Pediatr.* 

Takada. 1995. The cleavage and inactivation of plasminogen activator inhibitor type 1 by neutrophil elastase: the evaluation of its physiologic relevance in

inhibitors to inactivation by proteinases from S*taphylococcus aureus* and

H. Nagase. 1988. Inactivation of tissue inhibitor of metalloproteinases by

by reactive oxygen species generated by phagocytosing polymorphonuclear

oxidants suppress the elastase-inhibitory capacity of alpha1-proteinase inhibitor in

and S. J. Weiss. 1994. Oxidative dissociation of human alpha 2-macroglobulin

smoking on the functional activity of alpha1-protease inhibitor in bronchoalveolar

antiprotease deficiency in the lower respiratory tract of humans. *Science* 206: 1315-1316.

1983. Functional alpha-1-protease inhibitor in the lower respiratory tract of

Inhibition of human leukocyte elastase bound to elastin: Relative ineffectiveness and two mechanisms of inhibitory activity. *Am. J. Respir. Cell Mol. Biol.* 2: 263-269. [116] Bruch, M., and J. G. Bieth. 1986. Influence of elastin on the inhibition of leucocyte

elastase by alpha1-proteinase inhibitor and bronchial inhibitor. Potent inhibition of

Murphy. 1995. Binding of gelatinases A and B to type-1 collagen and other matrix


**5** 

*Bulgaria* 

**Chronic Obstructive Pulmonary Disease –** 

Cigarette smoking is clearly associated with the development of chronic airway obstruction pulmonary disease and is responsible for 80–90% of cases. However, only 15–20% of heavy smokers develop clinically significant airflow obstruction. In the rest pulmonary function remains within normal limits. Besides the risk factors that are involved in airway obstruction, the genetic predisposition is also considered a key factor. It modulates lung's response to cigarette smoke inhalation and the development of airway obstruction. In addition to smoke induced emphysema, genetic susceptibility leading to α1-antitrypsin deficiency is associated with the propensity for the development of early-onset, familial emphysema. Thus both environmental and genetic factors contribute to the pathogenesis of

The molecular basis for tobacco smoke-induced emphysema is poorly understood. To thoroughly unravel the cellular and molecular events or signaling pathways that may contribute to the pathogenesis of smoke-induced emphysema or COPD, gene expression profiling - serial analysis of gene expression (SAGE) and microarray analysis as well as proteomics have been recently applied. The gene expression profiles of lung tissues from control smokers (GOLD-0) and moderate (GOLD-2) COPD smokers identified numerous classes of genes, the expression of which is altered in COPD patients. These include genes encoding molecules for signal transduction, receptor function, growth factor, nuclear chromatin and DNA binding, adhesion and cytoskeleton, metabolism, matrix, cell cycle, and oxidative stress such as HSP70 protein, heme oxygenase (decycling) 1 (HO-1). The data from proteomics also confirms a large number of proteins related to cigarette smoke induced endoplasmic reticulum stress, repair/injury proteins, heat shock proteins, apoptosis and cell

COPD is obviously a disease of imbalance of proteins - oxi/antioxidant, protease/ antiprotease, apoptosis/proliferation, acetylases/deacetylases, that can no longer perform their proper function to keep the homeostasis in the new environmental settings of the

Molecular chaperones provide the functional activity of proteins, they counteract the formation of abberantly folded polypeptides and allow their correct refolding under stress

**1. Introduction** 

emphysema.

cycle responsible molecules.

oxidative stress.

Radostina Cherneva, Daniela Petrova and Ognian Georgiev

*Department of Internal Medicine Clinic of Pulmonology, Sofia* 

**Chaperonopathology** 

*University Hospital Alexandrovska,* 

necrosis: a role in chronic obstructive pulmonary disease? *Am. J Respir. Cell Mol. Biol* 37: 135-143.

