Mechanisms of emphysema in alpha1-antitrypsin deficiency: molecular and cellular insights.

The severe, early onset emphysema that occurs in patients with circulating deficiency of alpha(1)-antitrypsin (alpha(1)-AT) attests to the importance of this protease inhibitor in maintaining lung parenchymal integrity. It has led to the powerful concept of protease:antiprotease balance being crucial to alveolar homeostasis. Pathogenic mutations cause alpha(1)-AT to self-associate into polymer chains that accumulate intracellularly rather than proceeding along the secretory pathway. Polymerisation of alpha(1)-AT abolishes antiprotease activity and confers toxic gain-of-function effects. Since alpha(1)-AT is predominantly synthesised in the liver, where it does not play a major homeostatic role, the directly toxic effects of polymerisation are clearest here. However, data from molecular, cellular, animal and ex vivo studies indicate that intrapulmonary polymerisation of alpha(1)-AT and inflammatory positive feedback loops may augment the destructive effects of decreased antiprotease levels in the lung. This review integrates the findings from these different approaches and highlights how multiple pathways may converge to give the severe, panacinar emphysema phenotype seen in alpha(1)-AT deficiency.

Oxygen alert cards and controlled oxygen: preventing emergency admissions at risk of hypercapnic acidosis receiving high inspired oxygen concentrations in ambulances and A&E departments.

BACKGROUND: Appropriate resuscitation of hypoxic patients is fundamental in emergency admissions. To achieve this, it is standard practice of ambulance staff to administer high concentrations of oxygen to patients who may be in respiratory distress. A proportion of patients with chronic respiratory disease will become hypercapnic on this. OBJECTIVES AND METHODS: A scheme was agreed between the authors' hospital and the local ambulance service, whereby patients with a history of previous hypercapnic acidosis with a Pao2 >10.0 kPa--indicating that oxygen may have worsened the hypercapnia--are issued with "O2 Alert" cards and a 24% Venturi mask. The patients are instructed to show these to ambulance and A&E staff who will then use the mask to avoid excessive oxygenation. The scheme was launched in 2001 and this paper present the results of an audit of the scheme in 2004. RESULTS: A total of 18 patients were issued with cards, and 14 were readmitted on 69 occasions. Sufficient documentation for auditing purposes was available for 52 of the 69 episodes. Of these audited admissions, 63% were managed in the ambulance, in line with card-holder protocol. This figure rose to 94% in the accident and emergency department. CONCLUSION: These data support the usability of such a scheme to prevent iatrogenic hypercapnia in emergency admissions.

Inactive conformation of the serpin alpha(1)-antichymotrypsin indicates two-stage insertion of the reactive loop: implications for inhibitory function and conformational disease.

The serpins are a family of proteinase inhibitors that play a central role in the control of proteolytic cascades. Their inhibitory mechanism depends on the intramolecular insertion of the reactive loop into beta-sheet A after cleavage by the target proteinase. Point mutations within the protein can allow aberrant conformational transitions characterized by beta-strand exchange between the reactive loop of one molecule and beta-sheet A of another. These loop-sheet polymers result in diseases as varied as cirrhosis, emphysema, angio-oedema, and thrombosis, and we recently have shown that they underlie an early-onset dementia. We report here the biochemical characteristics and crystal structure of a naturally occurring variant (Leu-55-Pro) of the plasma serpin alpha(1)-antichymotrypsin trapped as an inactive intermediate. The structure demonstrates a serpin configuration with partial insertion of the reactive loop into beta-sheet A. The lower part of the sheet is filled by the last turn of F-helix and the loop that links it to s3A. This conformation matches that of proposed intermediates on the pathway to complex and polymer formation in the serpins. In particular, this intermediate, along with the latent and polymerized conformations, explains the loss of activity of plasma alpha(1)-antichymotrypsin associated with chronic obstructive pulmonary disease in patients with the Leu-55-Pro mutation.

Familial dementia caused by polymerization of mutant neuroserpin.

Aberrant protein processing with tissue deposition is associated with many common neurodegenerative disorders; however, the complex interplay of genetic and environmental factors has made it difficult to decipher the sequence of events linking protein aggregation with clinical disease. Substantial progress has been made toward understanding the pathophysiology of prototypical conformational diseases and protein polymerization in the superfamily of serine proteinase inhibitors (serpins). Here we describe a new disease, familial encephalopathy with neuroserpin inclusion bodies, characterized clinically as an autosomal dominantly inherited dementia, histologically by unique neuronal inclusion bodies and biochemically by polymers of the neuron-specific serpin, neuroserpin. We report the cosegregation of point mutations in the neuroserpin gene (PI12) with the disease in two families. The significance of one mutation, S49P, is evident from its homology to a previously described serpin mutations, whereas that of the other, S52R, is predicted by modelling of the serpin template. Our findings provide a molecular mechanism for a familial dementia and imply that inhibitors of protein polymerization may be effective therapies for this disorder and perhaps for other more common neurodegenerative diseases.

Conformational changes and disease--serpins, prions and Alzheimer's.

Some of the most perplexing disorders in medicine are each now known to arise from the conformational instability of an underlying protein. The consequence is a continuum of pathologies with typically a change in fold leading to ordered aggregation and tissue deposition. The serpins provide a structural prototype for these pathologies and give a perspective on the assessment of current proposals as to the conformational basis of both Alzheimer's disease and the transmissible prion encephalopathies.