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Wed, 18 Oct 2006 15:57:47 EDT

By Crystal Phend, MedPage Today Staff Writer

Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University

of California, San Francisco

October 17, 2006

MedPage Today Action Points Explain to interested patients that silicosis can be prevented by avoiding inhalation of silica, a major component of sand.

Review
YOKOHAMA, Japan, Oct. 17 -- The antioxidant enzyme heme oxygenase-1 may be a potential biomarker or even treatment for silicosis, according to researchers here.

Elevated heme oxygenase-1 levels appeared to identify patients with silicosis rather than all patients with impaired lung function, reported Yoshiaki Ishigatsubo, M.D., Ph.D., of the Yokohama City University here, and colleagues, in the Oct. 15 issue of the American Journal of Respiratory and Critical Care Medicine.

A serum biomarker for silicosis, caused by prolonged, occupational exposure to airborne crystalline silica in mines, foundries, and stone or glass manufacturing plants, could facilitate early diagnosis, Dr. Ishigatsubo said. Once in the lungs, silica increases production of reactive oxygen species, which induces airway inflammation and can cause scar tissue and oxidative DNA damage.

Heme oxygenase-1 levels were significantly higher in the lungs of patients with silicosis compared with those with chronic obstructive pulmonary disease (COPD) and healthy individuals (6.23 ng/mL versus 1.77 ng/mL and 2.75 ng/mL, respectively). Silicosis patients with only mildly impaired respiratory function showed the highest serum levels.

Greater expression was found with increasing forced expiratory volume in one minute (FEV₁, P=0.008) and with increasing vital capacity in these patients (P=0.046). However, the same was not true for patients with COPD, who have lung function similar to those with silicosis, or participants with normal lung function.

Levels of the enzyme decreased with increasing serum 8-hydroxydeoxyguanosine expression (P=0.035), which reflects silica-induced oxidative DNA damage and increased risk of cancer. Serum 8-hydroxydeoxyguanosine levels were significantly higher in patients with silicosis compared to healthy controls and COPD patients 0.280 ng/mL versus 0.189 ng/mL and 0.185 ng/mL, respectively).

Heme oxygenase-1 levels did not correlate with age, duration of silica exposure, smoking history, serum C-reactive protein, or occupational history in patients with silicosis.

Since increased heme oxygenase-1 can protect patients by suppressing silica-induced reactive oxygen species activity, upregulation of the enzyme "may represent a novel strategy for the treatment of silicosis," Dr. Ishigatsubo and colleagues wrote.

The study included 46 male patients (ages 56 to 83) diagnosed as having silicosis, on the basis of their occupational history and radiographs, as well as 27 men with COPD (age range 60 to 87) and 42 healthy male volunteers (age range 55 to 80).

As might be expected, the patients with silicosis and COPD had longer smoking histories than control subjects, but the majority of these were ex-smokers. Vital capacity or FEV₁ or both were less than 80% of predicted values in 21 of the 46 patients with silicosis, significantly lower than for control subjects. COPD patients had reduced FEV₁ but not vital capacity compared to controls.

The silicosis patients had varying radiographic severity:

• 28 had simple silicosis,
• 18 had complicated silicosis,
• 43 had an International Labor Organization radiographic opacity of 1/0 (with or without large opacities), and
• Four had large radiographic opacities only.

Some of the patients with impaired lung function due to silicosis or COPD were on theophylline (32.6% and 40.7%, respectively), short-acting beta-agonists (28.3% and 25.9%, respectively), anticholinergics (26.1% and 37.0%, respectively), or inhaled corticosteroids (8.7% and 22.2%, respectively). Silicosis patients had significantly higher serum C-reactive protein levels than patients with COPD or controls.

The researchers consistently found silica particles in lesions containing heme oxygenase-1 expressing cells when they performed immunohistochemical staining of tumor-free granulomatous tissue on lung tissue samples (two from patients with lung cancer and silicosis, eight from autopsied silicosis patients, and 17 controls). In this portion of the study, silicosis patients had significantly more cells expressing the enzyme than control subjects (409 positive cells per cm² versus 39 per cm², P=0.05)

This "indicates that silica exposure directly and persistently induces [heme oxygenase-1] expression in granulomatous lung tissue," Dr. Ishigatsubo and colleagues wrote.

There was no difference between heme oxygenase-1 expression in surgically resected and autopsied lung tissue (414 positive cells per cm² versus 407 per cm²), "suggesting that the terminal stage of disease did not affect expression of this protein," the investigators noted. However, lungs tissue from control subjects with non-pulmonary diseases expressed heme oxygenase-1 at levels "far below" those of silicotic lungs.

The researchers also found that silicosis airway inflammation in mice was suppressed by treatment with hemin, an inducer of heme oxygenase-1, and enhanced by zinc protoporphyrin, an inhibitor of heme oxygenase-1. Primary source: American Journal of Respiratory and Critical Care Medicine

Source reference:

Sato T, et al

Am J Respir Crit Care Med 2006; 174:906-914.

Department of Internal Medicine and Clinical Immunology, and Department of Pathology, Yokohama City University, Yokohama; Department of Pathology, Dokkyo University School of Medicine; Department of Internal Medicine, and Department of Radiology, Rosai Hospital for Silicosis, Tochigi; and Seamen's Insurance AMHTS Clinic, Yokohama, Japan Correspondence and requests for reprints should be addressed to Professor Yoshiaki Ishigatsubo, Department of Internal Medicine and Clinical Immunology, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan. E-mail:

Rationale: Heme oxygenase-1 (HO-1), a rate-limiting enzyme in heme catabolism, has antioxidative, antiapoptotic, and antiinflammatory activities. We examined whether HO-1 might be involved in silicosis.

Objectives: To investigate whether HO-1 can reduce silicosis in mice and humans.

Methods and measurements: Silicosis was studied using a murine model, and in 46 male patients. Serum HO-1 and 8-hydroxydeoxyguanosine (a marker of oxidative stress) were measured by enzyme-linked immunosorbent assay. Levels of HO-1 were measured by immunohistochemistry and immunoblotting.

Main results: Serum HO-1 levels were significantly elevated in patients with silicosis compared with age-matched control subjects or patients with chronic obstructive pulmonary disease. Serum HO-1 levels also correlated inversely with serum 8-hydroxydeoxyguanosine levels and positively with vital capacity and forced expiratory volume in one second in patients with silicosis. HO-1 was present in the lungs of humans and mice with silicosis, especially at sites of silica particle deposition. In mice, silica exposure was associated with acute leukocyte infiltration, leading to development of silicotic lung lesions. The inflammation was suppressed by treatment with hemin, an inducer of HO-1, and enhanced by zinc protoporphyrin, an inhibitor of HO-1.

Conclusions: Pulmonary HO-1 expression is increased in silicosis. HO-1 suppresses reactive oxygen species activity, and subsequent pathologic changes, thereby attenuating disease progression.

Key Words: antioxidants • occupational diseases • oxidative stress