Alpha₁-Antitrypsin Deficiency

Mal and colleagues reported a case of recurrence of pulmonary emphysema in a patient with ${alpha}$ ₁-antitrypsin deficiency. They described the case of a 49-year-old white man who underwent single lung transplantation for emphysema related to ${alpha}$ ₁-antitrypsin deficiency and to superimposed smoking. After several rejection episodes in the first year, the patient remained stable without evidence of graft dysfunction for more than 10 years, but he resumed light smoking at 8 years after transplant. At 11 years after transplant, recurrence of emphysema on the grafted side was diagnosed on computed tomography (CT) of the thorax, and 1 year later, the patient developed a moderate decline in lung function. A significant amount of unopposed elastase activity, possibly induced by smoking, has probably played a central role in the recurrence of emphysema.

To determine whether variations in the distribution of emphysema may be associated with discordance between airflow obstruction and impairment of gas exchange that usually occur in patients with COPD, Parr and colleagues used quantitative CT to assess emphysema severity and distribution in 119 subjects with ${alpha}$ ₁-antitrypsin deficiency (PiZ phenotype) and grouped them according to distribution pattern. In the 102 subjects with emphysema, they found that 65 had a predominantly basal pattern ("basal") and 37 (36%) had greater involvement of the upper regions ("apical"). As compared with subjects with apical distribution, subjects with basal distribution of emphysema had lower FEV₁ (mean difference, 9.9% predicted; 95% confidence interval, 3.8–16.0; p = 0.002) and milder impairment of gas exchange (Pa_O₂ mean difference, 0.5 kPa, 0.03–0.1; p = 0.016), as well as alveolar–arterial oxygen gradient (mean difference, 0.7 kPa; 0.2–1.2; p = 0.007). The authors concluded that the use of single physiologic parameters as a surrogate marker of emphysema severity may be misleading.

Gildea and coworkers used a Markov-based decision model to assess the cost-effectiveness of augmentation therapy for severe ${alpha}$ ₁-antitrypsin deficiency. A hypothetical cohort of 46-year-old patients with FEV₁ of 49% predicted was followed over time using a Monte Carlo simulation. Treatment for life cost $895,243 and yielded 7.19 quality-adjusted life-years. Treatment until FEV₁ was below 35% predicted cost $511,930 and produced 6.64 quality-adjusted life-years. No augmentation therapy costs $92,091 and yielded 4.62 quality-adjusted life-years. The incremental cost-effectiveness ratio was $207,841 per quality-adjusted life-year for augmentation therapy until FEV₁ reached below 35% predicted and $312,511 for augmentation therapy for life. The cost of augmentation therapy needed to be reduced from $54,765 to $4,900 for augmentation therapy for life to be considered cost-effective. The authors conclude that augmentation therapy in patients with ${alpha}$ ₁-antitrypsin deficiency is relatively cost-effective when compared with other conventionally used interventions.

Although serine elastase inhibitors have been proposed in the treatment of emphysema, little is known of their efficacy. To investigate this question, Churg and coworkers studied transgenic mice that produce extremely low levels of human ${alpha}$ ₁-antitrypsin and are tolerant to exogenous human ${alpha}$ ₁-antitrypsin (Prolastin). Mice were exposed to daily cigarette smoke for up to 6 months, and some mice received human ${alpha}$ ₁-antitrypsin every 48 hours. Treatment with ${alpha}$ ₁-antitrypsin produced about a 2-fold increase in serum levels of ${alpha}$ ₁-antitrypsin and elastase inhibitory capacity, and abolished smoke-induced increases in lavage neutrophils and matrix breakdown products (desmosine and hydroxyproline) at 2 to 30 days of smoke exposure. Oxidation of ${alpha}$ ₁-antitrypsin (to remove antiproteolytic activity) did not increase serum elastase inhibitory capacity but did prevent influx of neutrophils. Treatment with ${alpha}$ ₁-antitrypsin for 6 months provided 63% protection against airspace enlargement (emphysema) and abolished the increase in tumor necrosis factor- ${alpha}$ mediated by smoke. The authors conclude that treatment with ${alpha}$ ₁-antitrypsin ameliorates smoke-induced inflammation and matrix breakdown, possibly by suppressing tumor necrosis factor- ${alpha}$ , and provides partial protection against emphysema. An editorial commentary by Stockley accompanies this article.

The American Thoracic Society and the European Respiratory Society present a statement on standards for the diagnosis and management of ${alpha}$ ₁-antitrypsin deficiency.

In a mouse model of elastase-induced emphysema, Inoue and coworkers investigated the mechanism for increased susceptibility to bacterial infection. Intratracheal infection with Streptococcus pneumoniae (10³–10⁷ cfu per mouse) increased mortality in a dose-dependent manner in emphysematous mice, but did not kill control mice. Compared with control mice, the emphysematous mice had lower levels of total cells, neutrophils, tumor necrosis factor- ${alpha}$ , and macrophage inflammatory protein-2 in bronchoalveolar lavage. Histology revealed alveoli filled with inflammatory cells and exudates in the control mice, but not in the emphysematous mice. At 72 hours, the emphysematous mice had higher levels of serum cytokines, and significant numbers of S. pneumoniae in both lung tissue and blood. The authors conclude the experimental emphysema impairs the intra-alveolar, but not the systemic, immune response to bacterial infection.

In a pulmonary perspective, Suki and colleagues discuss the role of proteases, inflammation, and mechanical forces on the progression of emphysema.

It is not clear why neutrophil elastase activity is dominant in bronchial secretions of patients with bronchiectasis, given that the local environment is replete with antiproteases. In sputum samples from 10 patients with bronchiectasis, Chan and workers assessed whether components in the bronchial secretions bind neutrophil elastase and compromise the inhibitory efficiency of antielastases. In sputum sols from the patients, elastase activity was found in a polydisperse, alcian blue–stained zone of high molecular mass, suggesting that elastase was complexed with polyanionic partners. Western blot analysis revealed a polyanionic partner (heparan sulfate/syndecan-1) and physiological antielastases (secretory leukoproteinase inhibitor and ${alpha}$ ₁-antitrypsin) in the complex. After the elastase was dissociated from heparan sulfate/syndecan-1, it was fully inhibited by endogenous antielastases. (This effect contrasts with that of exogenous antielastases on elastase activity of sputum neutrophils.) Complexed elastase on blots of sputum sol was bound and inhibited by exogenous secretory leukoproteinase inhibitor but not by exogenous ${alpha}$ ₁-antitrypsin. The authors conclude that neutrophil elastase is found in bronchial secretions of patients with bronchiectasis as an active member of a supramolecular complex, which includes heparan sulfate/syndecan-1 and antielastases (secretory leukoproteinase inhibitor and ${alpha}$ ₁-antitrypsin), rather than as a free enzyme. An editorial commentary by Luisetti accompanies this article.

Citations 1-10 of 10 total displayed.

Pattern of Emphysema Distribution in ${alpha}$ 1-Antitrypsin Deficiency Influences Lung Function Impairment

David G. Parr, Berend C. Stoel, Jan Stolk, and Robert A. Stockley
Am. J. Respir. Crit. Care Med. 170: 1172 -1178. First published online as doi:10.1164/rccm.200406-761OC [Abstract] [Full text]

Recurrence of Pulmonary Emphysema in an ${alpha}$ -1 Proteinase Inhibitor-deficient Lung Transplant Recipient

Hervé Mal, Christophe Guignabert, Gabriel Thabut, Marie Pia d'Ortho, Olivier Brugière, Gaëlle Dauriat, Rolana Marrash-Chahla, Anne-Sophie Rangheard, Guy Lesèche, and Michel Fournier
Am. J. Respir. Crit. Care Med. 170: 811 -814. First published online as doi:10.1164/rccm.200312-1726CR [Abstract] [Full text]

American Thoracic Society/European Respiratory Society Statement: Standards for the Diagnosis and Management of Individuals with Alpha-1 Antitrypsin Deficiency

Am. J. Respir. Crit. Care Med. 168: 818-900. [Full text]

On the Progressive Nature of Emphysema: Roles of Proteases, Inflammation, and Mechanical Forces

Béla Suki, Kenneth R. Lutchen, and Edward P. Ingenito
Am. J. Respir. Crit. Care Med. 168: 516-521. [Full text]

You May Say That I Ain't Free—But It Don't Worry Me

Maurizio Luisetti
Am. J. Respir. Crit. Care Med. 168: 144-145. [Full text]

"Knock-out" Mouse: Down But Not Out

Robert A. Stockley
Am. J. Respir. Crit. Care Med. 168: 145-146. [Full text]

Sputum Sol Neutrophil Elastase Activity in Bronchiectasis: Differential Modulation by Syndecan-1

Stanley C. H. Chan, Daisy K. Y. Shum, and Mary S. M. Ip
Am. J. Respir. Crit. Care Med. 168: 192 -198. First published online as doi:10.1164/rccm.200208-829OC [Abstract] [Full text]

${alpha}$ -1-Antitrypsin Ameliorates Cigarette Smoke–induced Emphysema in the Mouse

Andrew Churg, Rong D. Wang, Changshi Xie, and Joanne L. Wright
Am. J. Respir. Crit. Care Med. 168: 199 -207. First published online as doi:10.1164/rccm.200302-203OC [Abstract] [Full text]

Cost-Effectiveness Analysis of Augmentation Therapy for Severe ${alpha}$ ₁-Antitrypsin Deficiency

Thomas R. Gildea, Kenneth M. Shermock, Mendel E. Singer, and James K. Stoller
Am. J. Respir. Crit. Care Med. 167: 1387 -1392. First published online as doi:10.1164/rccm.200209-1035OC [Abstract] [Full text]

Impaired Pulmonary Inflammatory Responses Are a Prominent Feature of Streptococcal Pneumonia in Mice with Experimental Emphysema

Sumito Inoue, Hidenori Nakamura, Kazuhisa Otake, Hiroshi Saito, Kyoko Terashita, Jun Sato, Hiroaki Takeda, and Hitonobu Tomoike
Am. J. Respir. Crit. Care Med. 167: 764-770. [Abstract] [Full text]

Year in Review Home

Alpha1-Antitrypsin Deficiency

Alpha₁-Antitrypsin Deficiency