Alpha emphysema

Courtney M., Jallat S., Tessier L-H., Benavente A., Crystal R.G. Lecocq J-P. (1985) Synthesis in E. coli of alpha,-antitrypsin variants of therapeutic potential for emphysema and thrombosis. Nature, 313, 149-151. 

Carp, H., Miller, F., Hoidal, J.R and Janoff, A. (1982). Potential mechanism of emphysema alpha-l-antiprotease inhibitor recovered from lungs of cigarette smokers contains oxidised methionine and has decreased elastase inhibitory capacity. Proc. Natl. Acad. Sci. USA 79, 2041-2046. 

Alpha-1-Protease Inhibitor (Prolastin) [Respiratory Agent/Alpha Protease Inhibitor Replacement] Uses a,-Antit-rypsin deficiency panacinar emphysema Action Replace human aj-protease inhibitor Dose 60 mg/kg IV once/wk Caution [C, ] Contra Selective IgA deficiencies w/ known IgA antibodies Disp Inj SE Fever, dizziness, flu-like Sxs, allergic Rxns EMS Pt may have chronic lung Dz/damage, monitor resp status OD Not expected to produce life-threatening Sxs... 

NTOl8 Churg, A., R. D. Wang, C. Xie, and J. L. Wright. Alpha-1-Antitrypsin ameliorates cigarette smoke-induced emphysema in the mouse. Am J Respir Crit Care Med 2003 168(2) 199-207. 

Indications Replacement therapy in patients with congenital alpha-1 antitrypsin deficiency who have panacinar emphysema... 

Clinical pharmacology Alpha-1 antitrypsin deficiency is a chronic, hereditary, usually fatal, autosomal recessive disorder in which a low concentration of alphai-proteinase inhibitor is associated with slowly progressive, severe, panacinar emphysema that most often manifests itself in the third to fourth decades of fife. The pathogenesis of development of emphysema in alpha-1 antitrypsin deficiency is believed to be due to a chronic biochemical imbalance between elastase and alphai-proteinase inhibitor (the principal inhibitor of neutrophil elastase), which is deficient in alpha-1 antitrypsin disease. As a result it is believed that alveolar structures are unprotected from chronic exposure to elastase released from a chronic low-level burden of neutrophils in the lower respiratory tract, resulting in progressive degradation... 

Crystal, R. G. (1990). Alpha 1 -antitrypsin deficiency, emphysema, and liver disease Genetic basis and strategies for therapy. J. Clin. Invest. 85, 1343-1352. 

Alpha-1 -antitrypsin emphysema, CF oxytocin hormone replacement... 

Obstructive lung disease is commonly associated with smoking or prolonged exposure to industrial smokes and fumes. The destruction of lung tissue in emphysema is permanent and irreversible and development ofthe condition is linked to deficiency of alpha-1-antitrypsin (a i-antitrypsin). 

The function of alpha-1-antitrypsin (a j-antitrypsin) is to oppose the activity of elastases, which are released into lung tissues during the inflammatory process. Lack of this inhibitor allows the elastases to destroy the elastic tissues of the lung, resulting in breakdown of alveolar walls, which accounts for the development of emphysema in some people who have never smoked. 

Alpha-1-antitrypsin mutations are associated with early-onset emphysema and liver disease that results in early death (50). The Z-variant of the disease is the most common and is present in over 95% of cases. This variant has been shown to be rescued in vitro by treatment with proteasome inhibitors (50). Several chemical and pharmacological chaperones have also been shown to correct the secretion of the mutant protein, which include the glucosidase inhibitor castanospermine, as well as the mannosidase inhibitors kifunensine (Fig. 2b)... 

Burrows JA, Willis LK, Perlmutter DH. Chemical chaperones mediate increased secretion of mutant alpha 1-antitrypsin (alpha 1-AT) Z A potential pharmacological strategy for prevention of liver injury and emphysema in alpha 1-AT deficiency. Proc. Natl. Acad. Sci. U.S.A. 2000 97 1796-1801. 

In particular, excessive proteolysis of elastin by HLE has been implicated in pulmonary emphysema [19]. In this case, the imbalance appears to result from reduced levels of active extracellular alpha,-proteinase inhibitor (a,-PI), the primary plasma inhibitor of HLE. This decrease is caused either by a genetic disorder (PiZZ phenotype individuals) or by reduction in the elastase inhibitory capacity (EIC) of ai-PI due to its oxidative inactivation by tobacco smoke [20]. The detailed evidence supporting the potential role of elastase in the development of emphysema has been extensively reviewed [21] and will not be repeated here. The fact that HLE is also a potent secretagogue [22] may play a role in several disease states, including cystic fibrosis [23], chronic bronchitis [24], and acute respiratory distress syndrome (ARDS) [25]. The mechanism of the secretagogue activity is not known, but, since the HLE-induced secretion can be blocked by specific HLE inhibitors, it appears to require catalytic activity by the enzyme [26]. 

The combination of MALDI-TOF MS and capillary LC/MS/MS was recently described for the identification of disease state markers in human urine. In this study, urine proteins obtained from emphysema patients were separated on 2-D gels and selected spots were digested with trypsin and analyzed by MALDI-TOF. A database search using Protein Prospector identified a potential biomarker for emphysema as human alpha-1-antitrypsin (AlAT). The corresponding MALDI spectrum contained nine out of 18 peptides with masses that match the expected tryptic digest fragments for AlAT. 

A 40-year-old man with cough, shortness of breath, and fever progressed to respiratory failure. He had smoked cocaine for the previous 17 years. His tobacco history was not known. His medical history included recurrent respiratory tract infections. A chest X-ray and CT scan showed findings consistent with bilateral bullous emphysema with a right lung abscess. He was ventilated and given antibiotics but died from respiratory failure secondary to pneumonia. Sputum cultures were positive for Enterobacter cloacae and Streptococcus species. Alpha-1 antitrypsin deficiency was ruled out. 

Alpha 1 antitrypsin (AAT) deficiency leads to lung destruction and the formation of emphysema by uncontrolled neutrophil elastase. Replacement of AAT by recombinant AAT (rAAT) given intravenously (IV) is the currently accepted treatment. Early evaluation of aerosolized AAT documented adequate alveolar fluid AAT and penetration into the lung interstitum [145]. A neutrophil elastase... 

USA Alpha-1 antitrypsin protein Aralast Respitin Human plasma-derived alpha-1 antitrypsin, non-recombinant Emphysema... 

Alpha 1-antitrypsin deficiency Patients with deficiency of the protease inhibitor, alpha 1-antitrypsin, may present with liver disease in childhood or with pulmonary emphysema in adults. All patients with genotypes associated with low alpha 1-antitrypsin in the serum are likely to develop emphysema if they smoke or are exposed to environmental pollutants... 

Alpha,-proteinase inhibitor inhibits serine proteases (e.g., neutrophil elastase), which are capable of degrading protein components of the alveolar walls and which are chronically present in the lung. Alpha,-proteinase inhibitor is indicated in chronic augmentation therapy in patients with congenital deficiency if a,-PI with clinically evident emphysema. 

A87. Pryor, W.A. The free radical chemistry of cigarette smoke and the inactivation of alpha-1-proteinase inhibitor in Pulmonary emphysema and proteolysis, edited by J.C. Taylor and C. Mittman, Academic Press, New 27A103. York, NY (1987) 369-392. 

Emphysema is caused by smoking cigarettes, by inhaling contaminants from the environment, or by the lack of the alpha -antitrypsin protein. The lung contains bacteria that release proteol5dic enzymes that destroy alveoli. The alphaj-antitrypsin protein inhibits proteolytic enzymes and protects the alveoli. 

Although the vast majority of cases of emphysema do not have alpha-l-antitrypsin deficiency, it is possible that an overwhelming local concentration of proteases may be beyond the body s capability to counter with anti-proteases. There is evidence that elastases are important in this process. 

GLASSIA Alphal-Proteinase Inhibitor (Human) Treatment of chronic augmentation and maintenance therapy in individuals with emphysema due to congenital deficiency of alpha-1-proteinase inhibitor (alpha 1-PI), also known as alphal-antitrypsin 125325/0 Kamada Ltd. Beit Kama, 7 Sapir St Kiryat Weitzmann, Science Park P.O. Box 4081 Ness Ziona 74140 Israel License 1826 7/1/2010... 

The most important differential diagnoses for LAM are Langerhans cell histiocytosis, idiopathic pulmonary fibrosis, and panlobular emphysema. In contrast to LAM, in Langerhans cell histiocytosis, the costophrenic sulci are usually spared, the cysts can be thick-waUed and irregularly outlined, and nodules are predominant in the early stage of disease. Idiopathic pulmonary fibrosis shows a volume loss in contrast to LAM, and the honeycomb cysts are predominantly located in the lower lobes and subpleural (Bonelli et al. 1998). Panlobular emphysema is associated with alpha-1-antiprotease deficiency. The most distinct feature of emphysema is the absence of defined walls in the areas of low attenuation, whereas cysts in LAM almost invariably present with walls (Johnson 1999). 

Sandstrdm CS, Piitulainen E, Janciauskiene S. Augmentation therapy in emphysema patient with ZZ alpha-1-antitrypsin deficiency. Respir Med 2008 1(2) 153-7. 

Worker 3 has large lungs, airflow obstruction, which reverses on inspiration, and a very low gas transfer. These are the features of emphysema, confirmed by thin-section CT. Emphysema due to occupational causes is not well established, the most specific cause is cadmium exposure (Davison et al. 1988). The lack of smoking, the normal alpha-one antitrypsin and the cadmium fume exposure make cadmium the most likely cause of his disease. In my... 

---