The proteinase-antiproteinase theory of emphysema: a speculative analysis of recent advances into the pathogenesis of emphysema.

This review concerns the reasons why only an estimated 10-15% of patients with alpha-1-antitrypsin (A1AT) deficiency develop the destructive lung disease known as emphysema. The arguments presented revolve around the proteinase-antiproteinase balance in the 'microenvironment' of the epithelial space of the lung. Attention is focused on the balance between destructive enzymes such as neutrophil elastase and protective proteins such as A1AT, secretory leucocyte proteinase inhibitor (SLPI), human elastase inhibitor (HEI) and elafin. When neutrophil elastase is already attached to the elastin fibres the smaller molecules SLPI and elafin appear to be better inhibitors of this enzyme than larger inhibitors such as A1AT and HEI. Furthermore, SLPI and elafin may provide the first line of defence against proteinase attack from neutrophil elastase. In trying to explain the variability in the clinical expression of A1AT-deficiency and the development of emphysema, the importance of changes to A1AT, SLPI and elafin molecules induced by smoking and/or oxygen free radicals has been considered. It is possible that emphysema only develops in patients who have SLPI/elafin deficiency as well as A1AT deficiency.

Function of a rare variant of alpha-1-antitrypsin, phenotype P(i) EFranklin S, a poor inhibitor of human neutrophil elastase.

A 31-year-old woman with the rare alpha-1-antitrypsin (A1AT) phenotype P(i) EFranklin S presented to this laboratory. Since little is known about the EFranklin protein, a study was established to investigate the biochemical properties of this glycoprotein, notably its inhibitory activity against human neutrophil elastase (HNE), compared with that of the more common A1AT variants M and Z. The serum A1AT level of 1.8 g/l (reference range 0.8-2.2 g/l) and anti-neutrophil elastase capacity (ANEC) value of 28 microM (reference range 15-42 microM) of this variant were normal. However, the association rate constant (AC) of the isolated and purified EFranklin protein 2.7 (0.4) x 10(6) M-1 s-1 at 25 degrees C was significantly lower compared with that in the normal M variant 9.1 (0.9) x 10(6) M-1 s-1. This implies that this form of A1AT is expressed at normal levels in serum but is functionally impaired as an inhibitor of HNE. The in vivo serum inhibition time of HNE was estimated to be 66 ms for the purified EFranklin protein compared with 20 ms for the M protein. While this protein is not an efficient inhibitor of HNE, there are sufficient molecules in the serum to achieve 100% inhibition of HNE and to protect the lung against proteinase attack. In conclusion, individuals who inherit the rare EFranklin variant in conjunction with the M or S A1AT molecules do not appear to have a high risk for the development of emphysema.

Kinetic characterisation of alpha-1-antitrypsin F as an inhibitor of human neutrophil elastase.

Patients homozygous for the Z allele of alpha-1-antitrypsin (alpha 1AT) have very low serum levels and are predisposed to emphysema. There have also been reports of emphysema being associated with the heterozygous phenotype FZ. To investigate whether F alpha 1AT was dysfunctional, the inhibitory activity of F alpha 1AT against human neutrophil elastase (HNE) was compared with that of common alpha 1AT phenotypes. Time-dependent inhibition of HNE by alpha 1AT was used to calculate the association rate constant (k assoc) for M, MZ, FM, FZ, F (partially purified from FZ or FS), Z and S alpha 1AT phenotypes in human sera. The results for k assoc at 25 degrees C were 9.1 (SD 0.9), 9.7 (SD 0.9), 8.0 (SD 0.8), 4.0 (SD 0.4), 4.2 (SD 0.8), 5.1 (SD 0.6) and 8.6 (SD 0.6) x 10(6) M-1s-1 respectively. F was found to have reduced activity much like that of Z, the alpha 1AT most commonly associated with emphysema. MZ (low risk for disease) and FZ heterozygotes had similar intermediate alpha 1AT levels. However the in vivo inhibition time for FZ was almost three times longer than for MZ, indicating greater exposure to proteolytic damage from free elastase for FZ than MZ individuals. In conclusion, F alpha 1AT is expressed in serum at low normal levels but is dysfunctional in its ability to inhibit HNE. Individuals who coinherit the F and a deficiency allele such as Z or Null, are likely to have a high risk for the development of emphysema. The disease risk for F homozygotes remains to be determined.

Asthma, allergy and atopy in Asian immigrants in Melbourne.

OBJECTIVES: To compare the prevalence of asthma, hay fever and atopy in Asian immigrants in Melbourne with that in Australian-born non-Asians and Australian-born Asians, and to investigate the association of these conditions with atopic status, length of stay in Australia and IgE levels in Asian immigrants. DESIGN: We performed a cross-sectional study by telephone interviews, using standard questionnaire items on respiratory and allergic symptoms. A random sample of 636 recent Asian immigrants of ethnic Chinese origin, 109 Australian-born Asians and 424 Australian-born non-Asians were selected from the 1991 Melbourne Telephone Directory, using a presumptive surname list. Skin tests to determine atopic status were performed on 269 Asian immigrants and 167 of these also had serum levels of total and specific IgE estimated. RESULTS: In the under 20 years age group the prevalence of wheeze or asthma ever was higher in Australian-born non-Asians and Australian-born Asians than in Asian immigrants (P < 0.001), and the prevalence of hay fever was higher in Asian immigrants and Australian-born Asians than in Australian-born non-Asians. In those older than 20 years, hay fever was almost twice as common in Asian immigrants as in Australian-born non-Asians (P < 0.001 for 20-40 years age group; P < 0.01 for > 40 years). The prevalence of hay fever and, to a lesser degree, asthma in Asian immigrants increased significantly with length of stay in Australia, independent of age at arrival, sex and atopic status (trend test: P < 0.001 for hay fever; P = 0.05 for asthma). Atopy was more common in Asian immigrants and Australian-born Asians than in Australian-born non-Asians (P < 0.001) and was very strongly associated with both hay fever and asthma, irrespective of length of stay. Pollen and mite sensitivities were more common in Asian subjects (twice as common for Asian-born and 1.5 times for Australian-born) than non-Asian subjects (P < 0.01). Among Asian immigrants, elevated total IgE level (> 100 IU/mL) was strongly associated with a history of hay fever (P < 0.01) and wheeze or asthma ever (P < 0.05), atopy (P < 0.001) and the presence of specific IgE antibodies to grass pollen, dust mite, cockroach and Ascaris antigens (P < 0.05 for all). CONCLUSION: We found substantial differences in the prevalence of asthma, hay fever and atopy between Asian immigrants, Australian-born Asians and non-Asians. The prevalence of hay fever and asthma in Asian immigrants was strongly associated with length of stay in Australia, suggesting that environmental factors are important in the pathogenesis of these diseases.

Chronic lung diseases and the perception of breathlessness: a clinical perspective.

Breathlessness is an extremely common symptom. Its genesis is incompletely understood but is known to be largely determined by many of the mechanical factors associated with the act of breathing. As with all subjective sensations various other factors including volition, behavioural style and other cortical and subcortical factors play a part in its genesis. The relief of breathlessness is primarily directed at the underlying disorder. In those conditions and situations where specific therapy has little to offer or little impact it is reasonable to consider ways of reducing the perception of breathlessness by pharmacological means. However, to date there is no convincing evidence that use of drugs in the pursuit of the relief of breathlessness has any specific effect in modifying the perception of this often distressing symptom. Any reduction in breathlessness achieved in this way can be adequately explained in terms of a reduction in ventilation and other indices of respiratory mechanics.

The 'shrinking lungs syndrome'--an infrequently recognised feature of systemic lupus erythematosus.

Two cases of the 'Shrinking Lungs Syndrome' in patients with systemic lupus erythematosus are described to highlight an infrequently recognised feature of this condition. Respiratory muscle weakness, improved by steroid therapy, was demonstrated in each patient and considered to be the mechanism underlying the respiratory symptoms.

Lung infection caused by Rhodococcus.

We report a case of lung infection, clinically resembling tuberculosis, caused by Rhodococcus rubropertinctus. The patient had no apparent immunosuppression which is unusual for disease caused by the 'rhodochrous' complex. The infection responded successfully to oral anti-tuberculous therapy, which included rifampicin, and to oral tetracycline.