Clinical Features and History of the Destructive Lung Disease Associated with Alpha-1-Antitrypsin Deficiency of Adults with Pulmonary Symptoms

Brantly, Mark; Paul, Lester D.; Miller, Bess; Falk, Roni T.; Wu, Margaret; Crystal, Ronald G.

doi:10.1164/ajrccm/138.2.327

Cited by 292 publications

(170 citation statements)

References 20 publications

Supporting

Mentioning

153

Contrasting

Unclassified

Order By: Relevance

“…For treatment of CF airway disease, delivery of a normal copy of the CF transmembrane conductance regulator gene to the defective airway epithelium should restore normal airway function (2). Likewise, for AAT deficiency, secretion of AAT from the gene-corrected airway epithelium should alleviate the development of emphysema (3).…”

Section: Microbiologymentioning

confidence: 99%

Adeno-associated virus serotype 9 vectors transduce murine alveolar and nasal epithelia and can be readministered

Limberis

Wilson

2006

Proc. Natl. Acad. Sci. U.S.A.

144

156

View full text Add to dashboard Cite

Airway-directed gene transfer has emerged as a promising approach for the treatment of the two genetic diseases of the lung, namely cystic fibrosis and α-1-antitrypsin deficiency. Herein we describe the transduction efficiency of a novel adeno-associated virus (AAV) vector, AAV2/9, across murine nasal and lung airway epithelia. At the peak of gene expression AAV2/9-mediated human α-1-antitrypsin gene expression in serum was ≈60-fold better than that of AAV2/5. We found that AAV2/9-mediated n LacZ gene transfer in nasal and lung airways was relatively stable for 9 months, suggesting that a progenitor airway cell population was transduced. Most interestingly, we show that AAV2/9 can be readministered in the presence of high levels of serum-circulating neutralizing antibodies as early as 1 month after initial exposure, with minimal effect on overall reporter gene expression, rendering it a promising gene transfer vector candidate for use in humans.

show abstract

Section: Microbiologymentioning

confidence: 99%

Adeno-associated virus serotype 9 vectors transduce murine alveolar and nasal epithelia and can be readministered

Limberis

Wilson

2006

Proc. Natl. Acad. Sci. U.S.A.

144

156

View full text Add to dashboard Cite

show abstract

“…6,7 α1AT deficiency in combination with cigarette smoking is associated with a significantly reduced life expectancy. 8,9 In addition to this pulmonary disease which is usually not clinically manifest until the third decade of life a minority of the α1AT-deficient individuals develop symptoms and signs of liver disease during childhood, ranging from transient cholostatic icterus to complete liver cirrhosis. [10][11][12] A wide spectrum of mutations in the α1AT gene has been described 7,13 and many of them are associated with severe α1AT deficiency and COPD.…”

Section: Introductionmentioning

confidence: 99%

Molecular characterisation of the defective α1-antitrypsin alleles PI Mwürzburg (Pro369Ser), Mheerlen (Pro369Leu), and Q0lisbon (Thr68lle)

et al. 1999

View full text Add to dashboard Cite

Deficiency of the serine proteinase inhibitor (serpin) α1-antitrypsin (α1AT) is the most common autosomal recessive genetic disorder in Northern Europe. α1AT is the physiological regulator of the proteolytic enzyme neutrophil elastase and severe deficiency states are associated with an increased risk of developing chronic obstructive pulmonary disease (COPD) as a consequence of chronic proteolytic damage to the lungs. Among the known mutations of the α1AT gene causing severe α1AT deficiency and COPD a few alleles are also associated with liver disease. When expressed in cell cultures, all these particular alleles cause intracellular α1AT accumulation which appears to be a prerequisite for the development of hepatic injury. Liver disease is seen in only a small fraction of all patients carrying such alleles, however. The reason for this is not completely clear, but there is evidence that PI ZZ individuals 'susceptible' to liver disease carry an additional defect affecting protein degradation in the endoplasmic reticulum (ER). We characterise a newly identified defective http://www.stockton-press.co.uk/ejhg Mheerlen α1ATs are completely retained within synthesising cells, and the molecular defect of transportation in these two alleles may be similar to that in the common PI Z allele. The molecular defect in the PI Q0lisbon allele (Thr68Ile) shows similarity with the immediately neighbouring Mmineral springs mutation (Gly67Glu).

show abstract

“…Subjects with severe a 1 AT deficiency (PiZ phenotype; serum a 1 AT concentration <11 mM, likely to be 22 homocygotes) have decreased (~15±20% normal) circulating [18], and alveolar [17] concentrations of a 1 AT, which facilitates the development of early onset and rapidly progressive emphysema [19]. Around 30±40% [19] of patients also have chronic bronchitis [20], although the nature of the inflammation in the larger airways has not been studied in these individuals.…”

mentioning

confidence: 99%

“…Around 30±40% [19] of patients also have chronic bronchitis [20], although the nature of the inflammation in the larger airways has not been studied in these individuals.…”

mentioning

confidence: 99%

Airways inflammation in chronic bronchitis: the effects of smoking and alpha1-antitrypsin deficiency

Hill¹,

Bayley²,

Campbell³

et al. 2000

Eur Respir J

104

View full text Add to dashboard Cite

Airways inflammation in chronic bronchitis is thought predominantly to be a direct consequence of neutrophil recruitment and release of elastase in response to factors such as cigarette smoke. The aims of this study were to assess the role of smoking and determine whether the serum elastase inhibitor α1‐antitrypsin (α1AT) influenced the process. Airways inflammation was compared between patients with chronic obstructive bronchitis with (n=39) and without (n=42) severe α1AT deficiency. The authors assessed the sputum concentration of the neutrophil chemoattractants interleukin‐8 (IL‐8) and leukotriene (LT)B4, myeloperoxidase (MPO) as a marker of neutrophil influx, neutrophil elastase activity and its natural inhibitors, α1AT and secretory leukoprotease inhibitor (SLPI). Finally serum α1AT was measured to determine the degree of protein leakage (sputum sol serum α1AT ratio). Compared to current smokers, the exsmokers had a lower concentration of the chemoattractant IL‐8 (p<0.05) and a lower MPO concentration, although this failed to reach conventional statistical significance (p=0.06). Patients with α1AT deficiency had greater inflammation in the larger airways with increased LTB4 (p<0.005), MPO (p<0.001), neutrophil elastase activity (p<0.01), protein leak (p<0.001), and were found to have a lower anti‐proteinase screen with both reduced sputum α1AT (p<0.001) and SLPI concentrations (p<0.05). The reduction in sputum interleukin‐8 levels in exsmokers may decrease neutrophil influx and thus explain the slower rate of neutrophil mediated progression of lung disease compared to subjects who continue to smoke. Patients with α1‐antitrypsin deficiency had greater inflammation suggesting that α1‐antitrypsin plays an important role in protecting the larger airways from the inflammatory effects of elastase activity and may explain their more rapid progression of disease.

show abstract

Clinical Features and History of the Destructive Lung Disease Associated with Alpha-1-Antitrypsin Deficiency of Adults with Pulmonary Symptoms

Cited by 292 publications

References 20 publications

Adeno-associated virus serotype 9 vectors transduce murine alveolar and nasal epithelia and can be readministered

Adeno-associated virus serotype 9 vectors transduce murine alveolar and nasal epithelia and can be readministered

Molecular characterisation of the defective α1-antitrypsin alleles PI Mwürzburg (Pro369Ser), Mheerlen (Pro369Leu), and Q0lisbon (Thr68lle)

Airways inflammation in chronic bronchitis: the effects of smoking and alpha1-antitrypsin deficiency

Contact Info

Product

Resources

About