A novel antiapoptotic role for α1-antitrypsin in the prevention of pulmonary emphysema

Irina Petrache, Iwona Fijalkowska, Lijie Zhen, Terry R. Medler, Emile Brown, Pedro Cruz, Kang Hyeon Choe, Laimute Taraseviciene-Stewart, Robertas Scerbavicius, Lee Shapiro, Bing Zhang, Sihong Song, Dan Hicklin, Norbert F. Voelkel, Terence Flotte, Rubin M. Tuder

Research output: Contribution to journalArticle

145 Citations (Scopus)

Abstract

Rationale: There is growing evidence that alveolar cell apoptosis plays an important role in emphysema pathogenesis, a chronic inflammatory lung disease characterized by alveolar destruction. The association of α1- antitrypsin deficiency with the development of emphysema has supported the concept that protease/antiprotease imbalance mediates cigarette smoke-induced emphysema. Objectives: We propose that, in addition to its antielastolytic effects, α1-antitrypsin may have broader biological effects in the lung, preventing emphysema through inhibition of alveolar cells apoptosis. Methods, Measurements, and Main Results: Transduction of human α1-antitrypsin via replication-deficient adeno-associated virus attenuated airspace enlargement and emphysema caused by inhibition of vascular endothelial growth factor (VEGF) receptors with SU5416 in mice, a model of apoptosis-dependent emphysema lacking neutrophilic inflammation. The overexpressed human serine protease inhibitor accumulated in lung cells and suppressed caspase-3 activation and oxidative stress in lungs treated with the VEGF blocker or with VEGF receptor-1 and -2 antibodies. Similar results were obtained in SU5416-treated rats given human α1-antitrypsin intravenously. Conclusions: Our findings suggest that inhibition of structural alveolar cell apoptosis by α1-antitrypsin represents a novel protective mechanism of the serpin against emphysema. Further elucidation of this mechanism may extend the therapeutic options for emphysema caused by reduced level or loss of function of α1-antitrypsin.

Original languageEnglish
Pages (from-to)1222-1228
Number of pages7
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume173
Issue number11
DOIs
StatePublished - Jun 1 2006

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Pulmonary Emphysema
Emphysema
Alveolar Epithelial Cells
Apoptosis
Lung
Serpins
Vascular Endothelial Growth Factor Receptor-1
Vascular Endothelial Growth Factor Receptor-2
Dependovirus
Vascular Endothelial Growth Factor Receptor
Serine Proteinase Inhibitors
Protease Inhibitors
Smoke
Tobacco Products
Caspase 3
Vascular Endothelial Growth Factor A
Lung Diseases
Oxidative Stress
Peptide Hydrolases
Inflammation

Keywords

  • Antiprotease
  • Caspase
  • Chronic obstructive pulmonary disease
  • Oxidative stress
  • Serpin

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

Cite this

A novel antiapoptotic role for α1-antitrypsin in the prevention of pulmonary emphysema. / Petrache, Irina; Fijalkowska, Iwona; Zhen, Lijie; Medler, Terry R.; Brown, Emile; Cruz, Pedro; Choe, Kang Hyeon; Taraseviciene-Stewart, Laimute; Scerbavicius, Robertas; Shapiro, Lee; Zhang, Bing; Song, Sihong; Hicklin, Dan; Voelkel, Norbert F.; Flotte, Terence; Tuder, Rubin M.

In: American Journal of Respiratory and Critical Care Medicine, Vol. 173, No. 11, 01.06.2006, p. 1222-1228.

Research output: Contribution to journalArticle

Petrache, I, Fijalkowska, I, Zhen, L, Medler, TR, Brown, E, Cruz, P, Choe, KH, Taraseviciene-Stewart, L, Scerbavicius, R, Shapiro, L, Zhang, B, Song, S, Hicklin, D, Voelkel, NF, Flotte, T & Tuder, RM 2006, 'A novel antiapoptotic role for α1-antitrypsin in the prevention of pulmonary emphysema', American Journal of Respiratory and Critical Care Medicine, vol. 173, no. 11, pp. 1222-1228. https://doi.org/10.1164/rccm.200512-1842OC
Petrache, Irina ; Fijalkowska, Iwona ; Zhen, Lijie ; Medler, Terry R. ; Brown, Emile ; Cruz, Pedro ; Choe, Kang Hyeon ; Taraseviciene-Stewart, Laimute ; Scerbavicius, Robertas ; Shapiro, Lee ; Zhang, Bing ; Song, Sihong ; Hicklin, Dan ; Voelkel, Norbert F. ; Flotte, Terence ; Tuder, Rubin M. / A novel antiapoptotic role for α1-antitrypsin in the prevention of pulmonary emphysema. In: American Journal of Respiratory and Critical Care Medicine. 2006 ; Vol. 173, No. 11. pp. 1222-1228.
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AU - Zhen, Lijie

AU - Medler, Terry R.

AU - Brown, Emile

AU - Cruz, Pedro

AU - Choe, Kang Hyeon

AU - Taraseviciene-Stewart, Laimute

AU - Scerbavicius, Robertas

AU - Shapiro, Lee

AU - Zhang, Bing

AU - Song, Sihong

AU - Hicklin, Dan

AU - Voelkel, Norbert F.

AU - Flotte, Terence

AU - Tuder, Rubin M.

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N2 - Rationale: There is growing evidence that alveolar cell apoptosis plays an important role in emphysema pathogenesis, a chronic inflammatory lung disease characterized by alveolar destruction. The association of α1- antitrypsin deficiency with the development of emphysema has supported the concept that protease/antiprotease imbalance mediates cigarette smoke-induced emphysema. Objectives: We propose that, in addition to its antielastolytic effects, α1-antitrypsin may have broader biological effects in the lung, preventing emphysema through inhibition of alveolar cells apoptosis. Methods, Measurements, and Main Results: Transduction of human α1-antitrypsin via replication-deficient adeno-associated virus attenuated airspace enlargement and emphysema caused by inhibition of vascular endothelial growth factor (VEGF) receptors with SU5416 in mice, a model of apoptosis-dependent emphysema lacking neutrophilic inflammation. The overexpressed human serine protease inhibitor accumulated in lung cells and suppressed caspase-3 activation and oxidative stress in lungs treated with the VEGF blocker or with VEGF receptor-1 and -2 antibodies. Similar results were obtained in SU5416-treated rats given human α1-antitrypsin intravenously. Conclusions: Our findings suggest that inhibition of structural alveolar cell apoptosis by α1-antitrypsin represents a novel protective mechanism of the serpin against emphysema. Further elucidation of this mechanism may extend the therapeutic options for emphysema caused by reduced level or loss of function of α1-antitrypsin.

AB - Rationale: There is growing evidence that alveolar cell apoptosis plays an important role in emphysema pathogenesis, a chronic inflammatory lung disease characterized by alveolar destruction. The association of α1- antitrypsin deficiency with the development of emphysema has supported the concept that protease/antiprotease imbalance mediates cigarette smoke-induced emphysema. Objectives: We propose that, in addition to its antielastolytic effects, α1-antitrypsin may have broader biological effects in the lung, preventing emphysema through inhibition of alveolar cells apoptosis. Methods, Measurements, and Main Results: Transduction of human α1-antitrypsin via replication-deficient adeno-associated virus attenuated airspace enlargement and emphysema caused by inhibition of vascular endothelial growth factor (VEGF) receptors with SU5416 in mice, a model of apoptosis-dependent emphysema lacking neutrophilic inflammation. The overexpressed human serine protease inhibitor accumulated in lung cells and suppressed caspase-3 activation and oxidative stress in lungs treated with the VEGF blocker or with VEGF receptor-1 and -2 antibodies. Similar results were obtained in SU5416-treated rats given human α1-antitrypsin intravenously. Conclusions: Our findings suggest that inhibition of structural alveolar cell apoptosis by α1-antitrypsin represents a novel protective mechanism of the serpin against emphysema. Further elucidation of this mechanism may extend the therapeutic options for emphysema caused by reduced level or loss of function of α1-antitrypsin.

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KW - Oxidative stress

KW - Serpin

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