M. X. FitzGerald

Systemic and pulmonary oxidative stress in idiopathic pulmonary fibrosis.

An oxidant/antioxidant imbalance has been proposed in patients with idiopathic pulmonary fibrosis (IPF). We tested this hypothesis by measuring various parameters of the oxidant/antioxidant balance in the plasma of 12 patients with IPF (7 nonsmokers and 5 smokers); in the bronchoalveolar lavage fluid (BALF) of 24 patients with IPF (17 nonsmokers and 7 smokers) and 31 healthy subjects (23 nonsmokers and 8 smokers). The trolox equivalent antioxidant capacity (TEAC) in plasma and BALF was lower in nonsmoking patients with IPF (plasma 0.55+/-0.1 mM, p<.001; BALF 4.8+/-1.2 microM, mean +/-SEM, p<.01), compared with healthy nonsmokers (plasma 1.33+/-0.03 mM; BALF 10+/-2 microM). Similar trends in plasma and BALF TEAC were observed in smoking patients with IPF in comparison with healthy smokers. The decrease in BALF TEAC was concomitant with a decrease in BALF protein thiol levels, but the decrease TEAC levels in plasma in IPF patients was not accompanied by a decrease in protein thiol levels. Reduced glutathione (GSH) was lower in BALF in nonsmoking patients with IPF (1.0+/-0.1 microM) compared with healthy nonsmokers (2.3+/-0.2 microM, p<.001). In contrast, GSH levels were higher in smoking patients with IPF (5.2+/-1.1 microM, p<.001) than in nonsmoking patients. GSSG levels were not different in any of the groups. The levels of products of lipid peroxidation measured as thiobarbituric acid reactive substances (TBARS) in plasma and BALF were significantly increased in both smoking (plasma 2.2+/-0.5 microM, p<.01; BALF 0.18+/-0.04 microM, p<.001), and nonsmoking (plasma 2.1+/-0.3 microM, p<.01; BALF 0.22+/-0.05 microM, p<.001) IPF patients, compared with healthy nonsmokers (plasma 1.4+/-0.3 microM; BALF 0.05+/-0.004 microM). These data show evidence of oxidant/antioxidant imbalance in the lungs of patients with IPF, which is also reflected as systemic oxidant stress.

Matrix metalloproteinases and tissue inhibitor of metalloproteinase-1 in sarcoidosis and IPF

The purpose of this study was to examine the role of interstitial collagenases, members of the family of matrix metalloproteinases, in the development of pulmonary fibrosis. The activity, levels and molecular forms of collagenases (matrix metalloproteinases (MMP)-1, -8 and -13), gelatinase B (MMP-9) and its main endogenous inhibitor, tissue inhibitor of metalloproteinase-1 (TIMP-1) were assessed in bronchoalveolar lavage fluid (BALF) from patients with idiopathic pulmonary fibrosis (IPF) and sarcoidosis patients with varying degrees of pulmonary parenchymal involvement. Collagenase activity was elevated in IPF and group 3 sarcoidosis patients. A positive correlation between BALF collagenase activity and MMP-8 levels was also observed. Western immunoblotting revealed the presence of two isoforms of MMP-8 in patient samples; an 80 kD form representing latent enzyme from polymorphonuclear neutrophils and a 55 kD form representing the fibroblast-type proform. MMP-9 levels were also elevated in both IPF and group 3 sarcoidosis patients, while TIMP-1 levels remained normal, indicating a shift in the balance between the enzyme and inhibitor, favouring MMP-9. Matrix metalloproteinase-8 is the major contributor to the bronchoalveolar lavage fluid collagenase activity in the airways of patients with idiopathic pulmonary fibrosis and sarcoidosis and may initiate collagen destruction and remodelling leading to the development of pulmonary fibrosis.

Prognostic value of bronchoalveolar lavage in sarcoidosis: the critical influence of disease presentation.

There has been considerable disagreement about the prognostic value of bronchoalveolar lavage lymphocyte measurements in patients with sarcoidosis. This study looks at the influence of the type of disease presentation and the time since onset of symptoms on lavage fluid lymphocyte profiles in 99 patients studied at the time of their initial diagnosis. Patients who had an acute inflammatory onset of disease with erythema nodosum (n = 32) or acute uveitis (n = 17) almost invariably had high T lymphocyte helper:suppressor (TH:TS) ratios (mean 10.1, 95% confidence interval 7.7-12.5) and had a higher proportion of T lymphocytes in cells obtained at lavage (40%, 35-46%) than patients with a pulmonary presentation (n = 38) (TH:TS 2.9, 0.2-5.7; T lymphocytes 21%, 15-27%) or those studied after resolution of erythema nodosum (n = 12). The patients with recent erythema nodosum had the highest TH:TS ratios of any group (10.4, 8.1-12.7). Thus lavage T lymphocyte percentage and TH:TS are highest in patients with sarcoidosis studied soon after an acute onset with an inflammatory condition such as erythema nodosum or uveitis. Patients with an acute onset of sarcoidosis have a better prognosis than those with a more insidious presentation. The major influence of type of disease presentation and, in the case of patients with erythema nodosum, of time since onset of symptoms may in part explain why different centres have reported such diverse results regarding the value of bronchoalveolar lavage in predicting outcome in sarcoidosis. Studies where the case mix of patients includes a high proportion of patients with acute onset will not find a high TH:TS ratio or increased numbers or proportions of lavage lymphocytes to be indicators of a poor prognosis.

High prevalence of familial sarcoidosis in an Irish population.

Previous studies in the Republic of Ireland have demonstrated a high national prevalence of sarcoidosis. Observations in our sarcoid clinic suggested a high prevalence of the disease among siblings and prompted a survey to quantify this phenomenon. The study group comprised 114 index patients with biopsy proved sarcoidosis and a total sibling pool of 534 individuals. Eleven of the index patients (9.6%) were found to have at least one sibling with sarcoidosis. Of the 13 siblings thus identified, eight had biopsy proof of the disease, while the remaining five showed highly suggestive clinical and radiological evidence of sarcoidosis. There was no significant difference in the mode of presentation between the sibling pairs or between familial and non-familial cases and there was an equal distribution of like sex and unlike sex pairs. In only two instances was the temporal profile of onset of the disease suggestive of intrafamilial spread of a transmissible agent. The high prevalence of sarcoidosis among siblings reported here (2.4%) suggests that genetic factors significantly predispose to the development of sarcoidosis and that family members of affected patients should be screened for this disease.

Atopy and bronchial reactivity in older patients with cystic fibrosis.

We studied 25 adolescent and adult patients with cystic fibrosis (CF) and 25 control subjects to determine if the prevalence of atopy and bronchial hyperreactivity was increased in this disease. Results showed that atopic symptoms, as defined by history, were more frequently present in the CF patients. Prick testing of the skin produced positive reactions in 88% of the CF group and 36% of the control subjects (p less than 0.001), and the mean number of reactions per subject was significantly higher in the former group (p less than 0.001); reactions to fungal antigens were strikingly positive in the CF group. The CF patients had a significantly higher mean serum IgG4 (p less than 0.001), IgE (p less than 0.01), and higher mean eosinophil count (p less than 0.05). Clear-cut bronchial hyperreactivity was demonstrated in the CF group compared with control subjects. Bronchial provocation with 400 micrograms of histamine led to a greater than 15% fall in the preinhalation FEV1 in 35% of the CF subjects compared with 4% of the control group, with a mean percentage fall of 15% and 3% respectively (p less than 0.001). In the CF group a greater than 15% rise in PEFR occurred in 32% after inhalation of the parasympatholytic, ipratropium bromide (54 micrograms), and in 27% after inhalation of the sympathomimetic, fenoterol (400 micrograms). No correlation was found between bronchial reactivity and atopic status, HLA phenotype pattern, or disease severity. The cause of the increased prevalence of atopy and bronchial reactivity in CF patients remains unknown. However, it is clear that a trial of bronchodilator therapy is warranted in adolescents and young adults with CF.

Patient work-up for bullectomy

A locali7ed area of hypertransradiance ofien leads to surgical refcrral. Among 608 cases. 115 were due to local lesions of airways, blood vessels, or parenchyma. Among the rema~ning 493 w~th bullae from diffuse emphysema, 21% underwent surgery. Good restoration of funct~on occurred in patients with rapidly progressive dyspnea who did not have a bronchitic component, recurrent infections, or CO? retention. Physiologically, preoperative findings suggestive of tension pneumothorax, ~ncluding aevere restriction, marked air trapping, and little ventilationlperfusion mismatch suggested good results. Favorable radiographic findings included well-defined, large air spaces without stlgmata of diffuse emphysema, serial films showing rapid enlargement of bullae, and expiration films with good thoracic motion and obscuration of lung around bullae. Compressed but otherwise intact lung was best demonstrated by angiography and CT scans. Palliative bullectomy in severe diffuse emphysema sometimes had gratifying clin~cal results. Resection of small bullae never caused Improvement. Localized giant bullae most often were associated with paraseptal or periacinar emphysema, and the best surgical results were obtained in thls group

Atopy, immunological changes, and respiratory function in bronchiectasis.

Cystic fibrosis has been reported to be associated with an increased prevalence of atopy and reversible airways obstruction. To determine whether such features can also result from other chronic suppurative lung infections, we studied 23 patients with proved bronchiectasis, and 23 age and sex matched normal controls. A personal or family history of atopy was reported with equal frequency in the two groups. Although the groups displayed a similar prevalence of positive immediate hypersensitivity skinprick test responses, the positive patients reacted to more antigens (p less than 0.05) and had larger weal diameters (p less than 0.01) than the positive controls. Other indices, such as blood eosinophil counts and serum IgE, did not differ significantly. Serum concentrations of immunoglobulins G, A, and M and of the four IgG subclasses tended to be higher in patients than controls, but only in the case of IgA (p less than 0.01) was this difference significant. No case of IgG subclass deficiency was noted. The patients displayed significant airflow obstruction, the mean basal one second forced expiratory volume (FEV1), forced vital capacity (FVC), and peak expiratory flow rate (PEFR) being 67%, 77%, and 67% of their predicted values. There was evidence of a significant reversible obstructive component in that FEV1 or PEFR or both increased by 15% or more in nine of the 23 patients after inhalation of fenoterol, the mean increases in FEV1, FVC, and PEFR for the whole group being 9.5%, 11%, and 16.9%. These results indicate that while bronchiectasis provokes a hyperimmune response it differs from cystic fibrosis in that there is no significant increase in the prevalence of atopy. The finding of reversible airways obstruction, however, suggests that bronchodilators may be useful adjuncts to treatment.

Hypoxaemia during chest physiotherapy in patients with cystic fibrosis

SummaryUsing ear oximetry, we studied the oxygen saturation in nine patients with cystic fibrosis who were undergoing chest physiotherapy. All nine subjects showed desaturation, seven to a level of less than 85%. Supplemental oxygen failed to prevent this but did promote a more rapid return to baseline. Chest physiotherapy is not without risk. Patients receiving such therapy require close observation and may benefit from supplemental oxygen.

Collagenase and fibronectin in bronchoalveolar lavage fluid in patients with sarcoidosis.

Bronchoalveolar lavage fluid from 43 patients with biopsy proved sarcoidosis and 10 control subjects were assayed for fibronectin and collagenase activity. Fibronectin was significantly increased in the group with sarcoidosis and was found to be positively correlated with angiotensin converting enzyme activity, protein concentration, percentage of T cells and helper:suppressor ratios in the lavage fluid. Increased fibronectin in the bronchoalveolar lavage fluid was not related to functional or radiographic indices of interstitial disease and did not identify patients subsequently requiring treatment. Latent collagenase was present in bronchoalveolar lavage fluid from 16 patients with sarcoidosis but not in any control sample. There was no association between the collagenase activity and the cell profiles of the lavage fluid. Yet carbon monoxide transfer factor was decreased in patients with bronchoalveolar lavage fluid collagenase. Ten of 16 patients with bronchoalveolar lavage fluid collagenase had radiographic class III or IV disease and a disease duration of more than two years. On follow up 62% of patients with bronchoalveolar lavage fluid collagenase required subsequent treatment, compared with only 23% of patients without collagenase. These results indicate an association between bronchoalveolar lavage fluid collagenase and progressive, prolonged disease in sarcoidosis, whereas increased bronchoalveolar lavage fluid fibronectin is associated with indices of disease activity.

Bronchoalveolar lavage in patients with mild and severe rheumatoid lung disease.

The reported prevalence of interstitial lung disease in patients with rheumatoid arthritis has varied from 10% to 50%, yet less than 5% of patients with arthritis develop severe fibrosing interstitial lung disease. This suggests that subclinical disease may not always presage progressive disease. Bronchoalveolar lavage fluid from patients with rheumatoid arthritis and either clinically evident interstitial lung disease or subclinical disease was examined for the presence of factors with a putative role in the development of interstitial fibrosis. Patients with subclinical disease were identified by prospective radiographic and lung function screening of 93 patients with rheumatoid arthritis. Fourteen patients were identified in this manner and an association between subclinical disease and smoking history was noted. Eleven patients with established interstitial lung disease had increased neutrophils (p less than 0.05), collagenase, and type III procollagen N terminal peptide levels (p less than 0.01) in the bronchoalveolar lavage fluid. Preliminary characterisation of the bronchoalveolar lavage collagenase suggested that it originated from neutrophils. Ten patients with subclinical interstitial lung disease underwent bronchoalveolar lavage. Of these, one had increased neutrophils and two had increased collagenase concentrations--abnormalities associated with advanced interstitial lung disease and a poor prognosis. These results suggest that in arthritis patients with evidence of subclinical pulmonary interstitial disease bronchoalveolar lavage might be useful in identifying those who may require careful monitoring in the hope that early treatment will prevent severe fibrosis.