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Exhaled Nitric Oxide Is Increased in Active Fibrosing Alveolitis^*

^* From the Departments of Thoracic Medicine (Drs. Paredi, Kharitonov, Loukides, and Barnes) and Occupational & Environmental Medicine (Drs. Pantelidis and du Bois), Imperial College School of Medicine at the National Heart and Lung Institute, London, UK. Supported by grants from the IRCCS University Respiratory Hospital Milan (Italy) and the British Lung Foundation (UK).

Correspondence to: Peter J. Barnes, MA, DM, DSc, Department of Thoracic Medicine, National Heart and Lung Institute, Dovehouse Street, London SW3 6LY, UK; e-mail: p.j.barnes{at}ic.ac.uk

	Abstract

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Study objectives: Interstitial inflammation is a major aggravating factor in fibrosing lung disease associated with scleroderma (FASSc) and cryptogenic fibrosing alveolitis (CFA). Exhaled nitric oxide (NO) production is increased in asthma and bronchiectasis and reflects the degree of inflammation. We investigated whether measuring levels of exhaled NO is valuable in assessing disease activity in patients with CFA and patients with FASSc.

Measurements and results: NO levels were measured in 11 patients with CFA (mean age ± SEM, 58 ± 12 years old; 5 were male) and 17 patients with FASSc (mean age, 48 ± 9 years old; 5 were male), and they were compared to BAL cell counts and lung function. Patients with CFA and FASSc had elevated NO levels (11.2 ± 1.0 parts per billion [ppb] and 9.8 ± 1.0 ppb, respectively; p > 0.05), whereas in a group of 13 nonsmoking normal subjects, the NO levels were not elevated (6.9 ± 0.5 ppb; p < 0.05). Patients with FASSc (n = 8) who had active BAL (defined as either lymphocytes > 14%, neutrophils > 4%, or eosinophils > 3%) had significantly higher NO levels (13.2 ± 1.8 ppb), and neutrophil (16.5 ± 4.0%) and lymphocyte (26.8 ± 3.4%) BAL cell counts than did patients with FASSc who had inactive BAL (6.7 ± 1.2 ppb; 1.3 ± 1.0% and 7.5 ± 1.3%, respectively; p < 0.05). There was a significant correlation between exhaled NO and lymphocyte cell count in patients with FASSc (r = 0.58; p < 0.05). All patients with CFA had active BAL; however, those treated with corticosteroids (12.9 ± 1.0% ppb, p < 0.05) had lower NO levels (9.0 ± 1 ppb) and higher BAL lymphocyte cell counts (16.6 ± 2.0%) than did those not treated with corticosteroids (7.2 ± 1.7%; p < 0.05).

Conclusions: We conclude that exhaled NO may be a useful addition to BAL cell counts in disease monitoring.

Key Words: fibrosing alveolitis • inflammation • nitric oxide

	Introduction

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In both cryptogenic fibrosing alveolitis (CFA) and fibrosing alveolitis associated with systemic sclerosis (FASSc), chronic inflammation and oxidative stress^{1 2} may be responsible for lung injury leading to pulmonary fibrosis,^{3 4 5} resulting in restrictive lung function and reduced gas transfer. Although they have a similar histologic appearance,⁶ the prognosis of CFA is worse than that of FASSc, with a mortality rate of 50% starting at 5 years from the onset of symptoms in patients with CFA, compared to roughly half that rate in patients with FASSc.^{7 8}

Nitric oxide (NO) is a gas produced by several types of pulmonary cells, including inflammatory, endothelial, and airway epithelial cells.⁹ Elevated levels of exhaled NO in asthma^{10 11} and bronchiectasis¹² are likely to be caused by the activation of the inducible form of NO synthase (iNOS)¹³ ; therefore, they reflect airway inflammation.

A significant increase in iNOS activity has been shown to occur in the lungs of patients with the early to intermediate stages of CFA.³ We hypothesized that patients with active BAL would have higher levels of exhaled NO, thereby reflecting the activity of airway inflammation.

	Materials and Methods

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Patients
Eleven patients with CFA (mean age ± SEM; 58 ± 12 years old; 5 were male) were included in the study on the basis of the following clinical diagnostic criteria for CFA¹⁴ : bilateral basal or widespread crackles on auscultation of the chest; a restrictive defect or a reduction in total gas transfer of CO (TLCO) on pulmonary function testing; CT abnormalities compatible with a diagnosis of fibrosing alveolitis^{15 16} ; and the absence of exposure to a recognized fibrogenic agent. Seventeen patients with FASSc (48 ± 9 years; 5 were male) met the American Rheumatism Association preliminary criteria for the diagnosis of scleroderma¹⁷ and also fulfilled the criteria for fibrosing alveolitis.¹⁴ Exclusion criteria included rheumatologic overlap syndrome, pulmonary hypertension, other respiratory diseases, and respiratory tract infection. None of the patients were current smokers, and smoking history was similar in the two disease groups (CFA and FASSc; Table 1 ). None of the patients were taking food supplements containing L-arginine, and none were on a nitrate-rich or nitrate-restricted diet that could influence exhaled NO levels.¹⁸ Patients were classified as having an active disease if their BAL was active and if they had worsening dyspnea during the month preceding the study. The patient's BAL was considered active if any one of the following criteria was met, each of which indicate abnormal inflammatory cell numbers¹⁹ : (1) lymphocytes of > 14%; (2) neutrophils of > 4%; and (3) eosinophils of > 3%. Five patients with CFA and five patients with FASSc were receiving steroid treatment (prednisolone, 30 mg/d). One patient with FASSc was receiving penicillamine treatment. In all patients, there were no echocardiographic signs of pulmonary hypertension (echocardiography was performed no later than 2 months before entering the study).

Thin-Section CT
CT sections were acquired by using a high-resolution fast scanner (Ultrafast CT; Imatron Inc; San Francisco, CA). While the patients were supine, interspaced 3-mm sections were obtained from the lung apices to the lung bases. Scans were analyzed by an experienced thoracic radiologist, and an assessment of the presence or absence of a pattern consistent with fibrosing alveolitis was made.

Bronchoscopy and BAL
Bronchoscopy and the BAL cell count were performed the same day that the patient gave informed consent. The procedures were performed after the exhaled NO was measured. BAL cell counts were assessed according to the criteria previously reported by Halsam et al.²⁰ BAL was considered to be active when any one of the following criteria was met, each of which indicates abnormal inflammatory cell numbers¹⁹ : (1) lymphocytes of > 14%; (2) neutrophils of > 4%; and (3) eosinophils of > 3%.

Exhaled NO Measurement
Exhaled NO was measured by using a modified chemiluminescence analyzer (model LR2000; Logan Research; Rochester, UK) that is sensitive to NO levels of 1 to 5,000 parts per billion (ppb) in volume and has a resolution of 0.3 ppb that was designed for on-line recording of exhaled NO concentration, as previously described by Kharitonov et al.²¹ The analyzer was calibrated by using certified NO mixtures (90 ppb and 436 ppb) in nitrogen (BOC Special Gases; Guildford, UK). Measurements of exhaled NO were made by slow exhalations (5 to 6 L/min) from the total lung capacity for 20 to 30 s against a resistance (3 ± 0.4 mm Hg).

Statistical Analysis
All of the results were expressed as mean ± SEM. Comparisons between groups were made by two-way analysis of variance with Bonferroni's correction for multiple comparisons. Linear regression analysis was used to assess the relationship between exhaled NO and BAL cell counts. All data were expressed as mean ± SEM. Significance of difference was defined as p < 0.05.

	Results

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All of the patients in the CFA and FASSc groups had CT scans consistent with fibrosing alveolitis. The criteria for BAL activity were met in all of the patients with CFA and in eight patients with FASSc who reported having worsening dyspnea in the month preceding bronchoscopy. The exhaled NO levels in patients with FASSc and CFA were similar (9.8 ± 1.0 ppb and 11.2 ± 1.0 ppb, respectively; p > 0.05; Fig 1 ), and they were significantly higher than those of a group of 13 nonsmoking healthy subjects (6.9 ± 0.5 ppb; p < 0.05). All of the patients with active FASSc and all but two patients with CFA had higher levels of exhaled NO than did patients in the healthy group. The exhaled NO levels were higher in patients with CFA than they were in patients with inactive FASSc (11.2 ± 1.0 ppb and 6.7 ± 1.0 ppb, respectively; p < 0.05). The untreated patients with CFA (Fig 2 , left[A] ) had higher NO levels (13.1 ± 1 ppb and 9.0 ± 1 ppb, respectively; p < 0.05) and lower BAL lymphocyte counts (7.2 ± 1.7% and 16.6 ± 1.8% respectively, p < 0.05) than did patients receiving steroid treatment (Fig 2 , right [B]), whereas there were no significant differences in symptoms and lung function test results between these two groups. The exhaled NO levels were significantly higher in patients with CFA receiving steroid treatment (9.0 ± 1 ppb) than they were in healthy subjects (6.9 ± 0.5 ppb; p < 0.05). Patients with active FASSc (n = 8), when compared to patients with inactive FASSc, had higher NO levels (13.2 ± 1.8 ppb and 6.7 ± 2.1 ppb, respectively; p < 0.05) and BAL neutrophil (16.5 ± 4.0% and 1.3 ± 1.0%, respectively; p < 00.5) and lymphocyte (26.8 ± 3.4% and 7.5 ± 2.0%, respectively; p < 0.05) cell counts (Fig 3 ). In patients with FASSc, the exhaled NO levels were correlated with BAL lymphocyte cell counts (r = 0.58, p < 0.05) but not with BAL neutrophil cell counts (r = 0.5; p > 0.05). The TLCO was lower in patients with active FASSc than it was in patients with inactive FASSc, but the difference between these groups (59 ± 7% and 63 ± 6%, respectively; p > 0.05; Table 1 ) was not statistically significant. The exhaled NO levels did not correlate with the severity of dyspnea in any group of patients.

View larger version (16K): [in this window] [in a new window] [Download PPT slide]   Figure 1. Levels of exhaled NO in normal subjects (), patients with CFA (), and patients with FASSc who had active (•) or inactive () BAL. p < 0.05 is a significance of difference between the groups.

View larger version (15K): [in this window] [in a new window] [Download PPT slide]   Figure 2. Exhaled NO levels and BAL cell counts in CFA. Left, A: patients who are not receiving steroid treatment. Right, B: patients who are receiving steroid treatment. p < 0.05 is a significance of difference between the groups.

View larger version (15K): [in this window] [in a new window] [Download PPT slide]   Figure 3. Left, A: exhaled NO levels and BAL cell counts in FASSc. Right, B: patients with active FASSc compared to patients with inactive FASSc. p < 0.05 is a significance of difference between the groups.

	Discussion

TOP Abstract Introduction Materials and Methods Results Discussion References

The inflammatory process underlying fibrosing alveolitis is sustained by the production of cytokines that favor inflammation, such as interleukin-1ß and tumor necrosis factor-.^{22 23} The induction of iNOS by these cytokines in macrophages, neutrophils, fibroblasts, and pneumocytes¹³ may explain the elevated levels of exhaled NO in patients with active diseases.

Our data are consistent with the findings of Saleh et al³ who demonstrated that an up-regulation of the inducible isoform of iNOS and an increased production of peroxynitrite occurs in the lungs of patients with mild and intermediate CFA. The initial activation of lung inflammatory cells, including alveolar macrophages, results in the release of cytokines that favor inflammation, such as interleukin-1ß and tumor necrosis factor-, which stimulate the production of NO by activating iNOS in the lung parenchyma. NO itself, when produced in high concentrations, might perpetuate the inflammatory process through a direct toxic action and through the production of peroxynitrite, which is potentially a potent cytotoxic molecule.^{24 25}

The prognosis of CFA is poor, with 50% of patients with CFA dying within 5 years of the onset of symptoms, whereas patients with FASSc have a better chance of survival.^{6 7 8} Although exhaled NO levels were similar in patients with CFA and FASSc, 9 of the 17 patients with FASSc had an inactive BAL and lower NO levels than did patients with CFA. This finding is consistent with the hypothesis that a more active inflammatory process in CFA may explain its accelerated progression.²⁶

To study the effect of treatment on NO levels and BAL cell counts, we divided the patients with CFA according to steroid treatment. In patients with CFA who were treated with steroids, lower NO levels were associated with a tendency toward lower BAL eosinophil cell counts and higher lymphocyte cell counts. These BAL characteristics are indicative of reduced disease activity and a better prognosis²⁷ ; therefore, exhaled NO measurements may be useful as an additional tool for assessing the disease activity in patients with CFA.

The results, which showed that patients with active FASSc exhaled higher levels of NO than did patients with inactive FASSc, indicate that NO may be a useful addition to the BAL cell count evaluation in characterizing disease activity. It is noteworthy that none of the patients evaluated in this study had echocardiographic signs of pulmonary hypertension, which has been recently associated with reduced exhaled NO levels.²⁸

The evaluation of exhaled NO may be a useful addition to the BAL cell count, not only because it can help to characterize the activity of the inflammatory process in the lungs of patients with interstitial lung disease, but also because it is noninvasive. The use of exhaled NO is a new noninvasive investigative tool that could add information to clinical assessments performed with radiology and invasive procedures, such as BAL cell counts, transbronchial biopsy, and open lung biopsy. The use of such a simple noninvasive measurement could help the clinician to understand the role of NO in the pathogenesis of interstitial lung disease and to assess disease control.

Because NO and its metabolites may play a role in the pathogenesis of interstitial lung disease, the use of specific iNOS inhibitors may become a future therapeutic option.

	Footnotes

 
Abbreviations: CFA = cryptogenic fibrosing alveolitis, FASSc = fibrosing alveolitis associated with scleroderma; iNOS = inducible form of nitirc oxide synthase; NO = nitric oxide; ppb = parts per billion; TLCO = total lung transfer for CO

Received for publication August 14, 1998. Accepted for publication December 8, 1998.

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This Article Abstract Full Text (PDF) Free Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Add to My Personal Article Archive Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (55) Citing Articles via Google Scholar Google Scholar Articles by Paredi, P. Articles by Barnes, P. J. Search for Related Content PubMed PubMed Citation Articles by Paredi, P. Articles by Barnes, P. J.