The alpha 1-antitrypsin gene and emphysema

1989 ◽  
Vol 257 (4) ◽  
pp. L147-L162 ◽  
Author(s):  
D. H. Perlmutter ◽  
J. A. Pierce
Keyword(s):  
Neutrophil Elastase ◽  
Tissue Injury ◽  
Biological Fluids ◽  
Clinical Manifestations ◽  
Serine Proteinase ◽  
Matrix Proteins ◽  
Major Objective ◽  
At Deficiency ◽  
Alpha 1 Antitrypsin ◽  
Supergene Family

alpha 1-Antitrypsin (alpha 1-AT) is the major endogenous inhibitor of neutrophil elastase. Individuals with alpha 1-AT deficiency are susceptible to premature development of emphysema. Thus a greater understanding of this serine proteinase inhibitor (serpin) has been a major objective of research on the pathogenesis of emphysema. In this article, we review recent literature on the alpha 1-AT gene and its relationship to other members of the serpin supergene family, particularly as it pertains to the function of alpha 1-AT. We also discuss the current literature on biosynthesis of alpha 1-AT and how its synthesis may be tightly regulated by the net balance of neutrophil elastase and alpha 1-AT at sites of inflammation/tissue injury. The net functional activity of alpha 1-AT in complex biological fluids is also affected by interaction with other enzymes, inhibitors, matrix proteins, and endogenous oxidants. Finally, we discuss the pathogenesis, clinical manifestations, and treatment of injury to the lung associated with deficiency variants of the alpha 1-AT gene.

A protein structural approach to the solution of biological problems: alpha 1-antitrypsin as a recent example

1993 ◽  
Vol 265 (3) ◽  
pp. L211-L219 ◽  
Author(s):  
D. A. Lomas ◽  
R. W. Carrell
Keyword(s):  
Endoplasmic Reticulum ◽  
Neutrophil Elastase ◽  
Serine Proteinase ◽  
Reactive Center Loop ◽  
Hepatocellular Damage ◽  
Reactive Center ◽  
Normal Gene ◽  
Alpha 1 Antitrypsin ◽  
And Function ◽  
Positively Charged

alpha 1-Antitrypsin is a circulating serine proteinase inhibitor that protects the lungs against proteolysis by the enzyme neutrophil elastase. Most northern Europeans have only the normal M form, but some 4% are heterozygotes for the Z deficiency mutant. This mutant is characterized by the substitution of a positively charged lysine residue for a negatively charged glutamic acid at position 342 and results in normal gene translation but reduced protein secretion into the plasma. The plasma levels of antitrypsin in homozygotes are only 15% of normal, the other 85% being retained in the endoplasmic reticulum of the hepatocyte. This review describes the effect of the Z mutation on the structure and function of antitrypsin and illustrates the importance of understanding protein structure in solving the mechanism of Z antitrypsin retention within the liver. We demonstrate that antitrypsin accumulation in the liver results from a unique interaction between antitrypsin molecules. The Z mutation perturbs the gap between the third and fifth strands of the A sheet, allowing the reactive center loop of one molecule to insert into the A sheet of a second. This loop-sheet polymerization results in the formation of chains of protein which form insoluble inclusions in the endoplasmic reticulum, resulting in hepatocellular damage and cirrhosis. In addition, the Z mutation results in a distortion of the circular dichroic spectrum, a rearrangement of the reactive center loop with respect to the A sheet, and a reduction in association rate constant with the cognate proteinase neutrophil elastase.

Nephrotic syndrome secondary to alpha-1 antitrypsin deficiency

2021 ◽  
Vol 14 (3) ◽  
pp. e240288
Author(s):  
Gabriela F Santos ◽  
Paul Ellis ◽  
Daniela Farrugia ◽  
Alice M Turner
Keyword(s):  
Nephrotic Syndrome ◽  
Membranous Nephropathy ◽  
Clinical Investigation ◽  
Genetic Disorder ◽  
Clinical Manifestations ◽  
Protective Role ◽  
Caucasian Woman ◽  
Antitrypsin Deficiency ◽  
Alpha 1 Antitrypsin Deficiency ◽  
Alpha 1 Antitrypsin

We report a 64-year-old caucasian woman diagnosed with membranous nephropathy secondary to alpha-1 antitrypsin deficiency (AATD). AATD is a rare autosomal codominant genetic disorder. Its clinical manifestations are mostly observed in the lungs, with early-onset emphysema. Nephropathy due to AATD is still very rare and only a few cohort studies have been reported. It has been recognised that alpha-1 antitrypsin has a protective role in the kidneys which enhances the possibility of development of kidney failure, such as nephrotic syndrome, in cases of AATD. Further clinical investigation is needed to understand the relationship between the development of nephropathy, namely membranous nephropathy, and AATD.

scholarly journals Complete primary structure of a calcium-dependent serine proteinase capable of degrading extracellular matrix proteins

FEBS Letters ◽  
1989 ◽  
Vol 250 (2) ◽  
pp. 411-415 ◽  
Author(s):  
Hirohisa Kinoshita ◽  
Hisako Sakiyama ◽  
Kastuo Tokunaga ◽  
Shinobu Imajoh-Ohmi ◽  
Yoshio Hamada ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Primary Structure ◽  
Serine Proteinase ◽  
Extracellular Matrix Proteins ◽  
Matrix Proteins ◽  
Calcium Dependent ◽  
Complete Primary Structure

scholarly journals Chronic Obstructive Lung Disease in young: Alpha 1 anti trypsin deficiency

2015 ◽  
Vol 3 (2) ◽  
pp. 65-67
Author(s):  
S.S. Dhakal ◽  
K.K. Agrawaal ◽  
N.K. Bhatta
Keyword(s):  
Bronchial Asthma ◽  
Clinical Manifestations ◽  
Lower Lobe ◽  
Chronic Obstructive Lung Disease ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Severe Deficiency ◽  
History Of ◽  
Pulmonary Arterial ◽  
Alpha 1 Antitrypsin

Alpha-1 antitrypsin (AAT) deficiency is a clinically under recognized inherited disorder. The main clinical manifestations relate to three separate organs: the lung, the liver, and the skin. In the lung, severe deficiency of AAT predisposes to chronic obstructive pulmonary disease. We present a case of 34 years male with a history of recurrent chest infections in past and treated in the line of bronchial asthma but not relieved. He was admitted on 22nd May 2011 at BPKIHS. He presented with type 2 respiratory failure and had features of severe pulmonary arterial hypertension and left lower lobe pneumonia. The patient got improved with the treatment and is doing well on follow up. The diagnosis should be strongly suspected in patients with history suggestive of bronchial asthma and with obstructive features.Journal of Advances in Internal Medicine 2014;3(2):65-67

scholarly journals Alpha-1 Antitrypsin and Monocytes

2015 ◽  
Vol 25 (2) ◽  
pp. 32-35
Author(s):  
Danielius Serapinas
Keyword(s):  
Experimental Investigation ◽  
Biological Activity ◽  
Proteinase Inhibitor ◽  
Serine Proteases ◽  
Serine Proteinase ◽  
Serine Proteinase Inhibitor ◽  
Short Term ◽  
Dual Effect ◽  
Soluble Cd14 ◽  
Alpha 1 Antitrypsin

Alpha-1 antitrypsin (AAT) is the main circulating serine proteinase inhibitor. A number of studies suggest that AAT can also exhibit biological activity independent of inhibition of serine proteases. The aim of the study was to make experimental investigation of AAT influence on monocytes stimulated by bacterial endotoxyn . AAT affects monocyte responses to LPS by regulating soluble CD14 release. Here we show that a short-term monocyte exposure to AAT leads to an increase of CD14 levels (p0.05). In parallel, a short-term cell exposure to AAT significantly enhances TNFα release. However, AAT was found to have a dual effect on LPS-induced TNFα release. Probably a rapid increase in AAT concentrations during various inflammatory and infectious conditions may enhance the magnitude of monocyte responses to endotoxin and subsequently accelerate resolution of the inflammatory reaction.

scholarly journals Increasing Neutrophil Elastase and Decreasing Its Inhibitor, Alpha 1-Antitrypsin, in Patients with Non-Alcoholic Fatty Liver Disease

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Maliheh Moradzadeh ◽  
Narjes Sargazi ◽  
Masoumeh Pourasgari ◽  
Sima Besharat ◽  
Samira Beygi ◽  
...  
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Neutrophil Elastase ◽  
Fatty Liver Disease ◽  
Alcoholic Fatty Liver ◽  
Alpha 1 Antitrypsin ◽  
Alcoholic Fatty Liver Disease

scholarly journals Effect of alpha-1 antitrypsin Portland variant (α1-PDX) on HIV-1 replication

2000 ◽  
Vol 352 (1) ◽  
pp. 91-98 ◽  
Author(s):  
Bouchaib BAHBOUHI ◽  
Mourad BENDJENNAT ◽  
Denise GUÉTARD ◽  
Nabil Georges SEIDAH ◽  
Elmostafa BAHRAOUI
Keyword(s):  
Viral Replication ◽  
Potential Role ◽  
Serine Proteinase ◽  
Recombinant Vaccinia Virus ◽  
Jurkat Cells ◽  
Serine Proteinase Inhibitor ◽  
Cdna Insert ◽  
Alpha 1 Antitrypsin ◽  
Hiv 1

The present work investigated the potential role of alpha-1 antitrypsin Portland variant (α1-PDX), a bioengineered serine proteinase inhibitor (serpin), in the interference with the viral replication of HIV-1, induction of syncytia and maturation of envelope glycoprotein gp160 to gp120 and gp41. A Jurkat lymphoid cell line transfected with a plasmid containing the α1-PDX cDNA (J-PDX) and expressing the protein in a stable manner was infected with HIV-1Lai. Controls were Jurkat cells transfected with the same vector pcDNA3 without the cDNA insert (J-pcDNA3). The results showed that viral replication of HIV-1 was significantly inhibited with a delay in replication kinetics in J-PDX cells as compared with J-pcDNA3 cells. In addition, a comparison of the infectious capacity of viruses produced in the presence and absence of α1-PDX revealed that this capacity differed. It was found that α1-PDX exerts its effect by interfering with the formation of syncytia between J-PDX cells infected with gp160 recombinant vaccinia virus, or after infection by HIV-1 and co-culture with uninfected Molt-4 cells. In contrast, when the same experiments were performed with J-pcDNA3 cells, a large number of syncytia was obtained. Analysis of viral proteins by Western blotting and densitometry showed that the inhibition of the cytopathic effect of HIV-1 and viral replication was correlated with the capacity of α1-PDX to interfere with the maturation of gp160 to gp120 and gp41.

Congenital Cytomegalovirus Infection: A Cause of Renal Dysplasia?

2007 ◽  
Vol 10 (4) ◽  
pp. 300-304 ◽  
Author(s):  
Maren Chan ◽  
Jonathan L. Hecht ◽  
Theonia Boyd ◽  
Seymour Rosen
Keyword(s):  
Viral Infections ◽  
Tissue Injury ◽  
Clinical Manifestations ◽  
Renal Dysplasia ◽  
Cmv Infection ◽  
Congenital Cytomegalovirus Infection ◽  
Congenital Cytomegalovirus ◽  
Wide Range ◽  
The Central Nervous System ◽  
Multicystic Dysplasia

Cytomegalovirus (CMV) infection is one of the most frequently encountered viral infections of the fetus and induces a wide range of histologic and clinical manifestations. Congenital abnormalities are typically restricted to the central nervous system despite evidence of CMV inclusions occurring in most epithelial cells. Although tissue injury and even glomerulonephritis have been observed in congenital CMV infections, renal multicystic dysplasia has not been reported. Herein, we describe a case of unilateral renal dysplasia in a 19-week fetus with concurrent CMV infection. We believe the present case to be the first description of a virus apparently inducing renal multicystic dysplasia.

Neutrophil Elastase and Alpha-1-Antitrypsin Binding in Monocyte Derived Microparticles

2019 ◽  
Author(s):  
P. Consiglio ◽  
E. Homsy ◽  
S. Das ◽  
M.C. Exline ◽  
C. McAtee ◽  
...  
Keyword(s):  
Neutrophil Elastase ◽  
Alpha 1 Antitrypsin
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