Collagen cross-linking was analyzed in lungs of rats, two, four, and ten weeks after intratracheal instillation of 1.5 units of bleomycin. Similar analyses were performed on lungs of mice 18 months after intratracheal instillation of bleomycin with or without subsequent exposure to 70% oxygen (O2) for 72 hours. Lungs were analyzed to determine the content of the reduced difunctional cross-links dihydroxylysinonorleucine (DHLNL) and hydroxylysinonorleucine (HLNL) and of the nonreducible trifunctional cross-link hydroxypyridinium (OHP). Ratios of DHLNL:HLNL were elevated in the rat lungs at two and four weeks, due to increased levels of DHLNL. There were no changes in the difunctional cross-links in any of the mouse lungs. Hydroxypyridinium content was elevated in the rat lungs at ten weeks and in the mouse lungs exposed to bleomycin and oxygen. We conclude that increases in DHLNL may serve as an early indicator that potentially "fibrotic collagen" is being synthesized in lungs acutely exposed to fibrogenic stimuli, while increases in OHP may serve as a permanent marker of a fibrogenic event that could have occurred months to years earlier.

Bronchopulmonary dysplasia (BPD), the most common cause of chronic lung disease in prematurely born infants, is histologically characterized by various degrees of airway and alveolar septal fibrosis. Tryptase, a serine protease specific to mast cells, has been shown to have potent fibroblast mitogenic properties and in addition has been shown to be increased in adult fibrotic lung disorders. Based on this analogy, the distribution of pulmonary mast cells exhibiting tryptase immunoreactivity was investigated by immunoperoxidase staining in autopsy specimens of infants dying with BPD. Morphologically normal lung specimens from similarly aged infants dying of sudden infant death syndrome (SIDS) served as controls. Tryptase-positive mast cell counts were performed at 250x from at least 10 random fields in bronchial, peribronchiolar, and alveolar regions. Compared to controls, in lung sections exhibiting typical histologic features of long-standing BPD, tryptase positive cells were significantly increased in bronchial (23.9 +/- 3.6 vs 14.4 +/- 2.3) and peribronchiolar (15.3 +/- 3.2 vs 4.63 +/- 0.6) regions compared to controls (P < 0.05, Student's t test). In particular, alveolar regions exhibiting moderate to severe degrees of septal fibrosis exhibited a dramatic increase in the number of tryptase-positive cells (9.83 +/- 1.89 vs 0.34 +/- 0.18, P = 0.003). These findings of a tryptase-positive mast cell hyperplasia in BPD suggest potential roles of mast cells as well as tryptase in the pathogenesis of this disease.

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The chronic pulmonary toxicity of beryllium sulfate was examined in rats over a 1-yr period after a single, 1-h exposure. Male rats, exposed in a nose-only inhalation chamber to an aerosol of 4.05 micrograms Be/L, were evaluated for lung toxicity by the methods of bronchoalveolar lavage, lung cell kinetics, and histopathologic analysis. Bronchoalveolar lavage activities for alkaline phosphatase (Alk Pase) and acid phosphatase (Ac Pase) were elevated 3 wk after exposure; lactate dehydrogenase (LDH) and Alk Pase activities peaked 3 months after exposure. Histopathologic analysis revealed progressive focal interstitial pneumonitis with a prominent alveolar component of heteromorphic macrophages, neutrophils, and debris. No increase was noted in the overall labeling index in the alveolar cell population at any of the time points sampled. This study demonstrates the effectiveness of bronchoalveolar lavage fluid analysis in monitoring lung damage over a prolonged period and shows that the pulmonary toxicity of beryllium manifests itself as a progressive lesion from a single 1-h inhalation exposure to BeSO4.