Characteristics of surfactant proteins in tumorigenic and inflammatory lung lesions in rodents

Abstract

Surfactant proteins (SPs) are essential for the proper structure and respiratory function of the lungs. There are four subtypes of SPs: SP-A, SP-B, SP-C, and SP-D. The expectorant drug ambroxol hydrochloride is clinically used to stimulate pulmonary surfactant and airway serous secretion. In addition, previous studies showed that ambroxol regulated SP production and attenuated pulmonary inflammation, with ambroxol hydrochloride being found to suppress quartz-induced lung inflammation via stimulation of pulmonary surfactant and airway serous secretion. In this study, we investigated the expression of SP-A, SP-B, SP-C, and SP-D in neoplastic and inflammatory lung lesions in rodents, as well as their possible application as potential markers for diagnostic purposes. SP-B and SP-C showed strong expression in lung hyperplasia and adenoma, whereas SP-A and SP-D were expressed in the mucus or exudates of inflammatory alveoli. Rodent tumorigenic hyperplasic tissues induced by various carcinogens were positive for napsin A, an aspartic proteinase involved in the maturation of SP-B; this indicated a focal increase in type II pneumocytes in the lungs. Therefore, high expression of napsin A in the alveolar walls may serve as a useful marker for prediction of the tumorigenic potential of lung hyperplasia in rodents.

Keywords: ambroxol hydrochloride; hyperplasia; lungs; napsin A; surfactant protein.

Fig. 1.

Histopathological findings in quartz-induced inflammatory lesions in F344 rat lungs (H & E). A, lungs treated with 0 ppm ambroxol hydrochloride; and B, lung treated with 120 ppm ambroxol hydrochloride. The figure shows neutrophil and histiocytic macrophage infiltration (A), whereas treatment with 120 ppm ambroxol hydrochloride decreased all these inflammatory signs (B).

Fig. 2.

Histopathological and immunohistochemical findings in quartz-induced inflammatory lesions in F344 rat lungs (×200). A, H & E; B, SP-A; C, SP-B; D, SP-C; and E, SP-D. The figure shows strongly positive staining in the alveolar mucus (B and E), alveolar and bronchial epithelial cells (C), and alveolar epithelial cells (D).

Fig. 3.

Histopathological and immunohistochemical findings in DHPN-induced proliferative lesions, hyperplasias, and adenomas in F344 rat lungs (×200). A, H & E; B, SP-A; C, SP-B; D, SP-C; and E, SP-D. The figure shows weak expression (+) of SP-A (B), strong (++) expression of SP-B (C), strong expression (++) of SP-D (D), and almost no expression (−) of SP-D (E).

Fig. 4.

Histopathological findings of Napsin A in hyperplasia or adenomas in F344 rat lungs. A, napsin A expression 12 weeks after treatment with NNK; B, napsin A expression 12 weeks after treatment with DHPN; C, napsin A expression 30 weeks after treatment with NNK and quartz; D, napsin A expression 30 weeks after treatment with DHPN. In proliferative lesions, including hyperplasias, the alveolar walls are strongly positive for napsin A (B and D), whereas in inflammatory lesions, the macrophages in the alveoli are positive for napsin A, although the alveolar walls of the alveoli are less stained (A and C).

Fig. 5.

Summary of features for discrimination of lung hyperplasias. Alveolar wall thickening because of inflammation is a reaction of inflammatory cells or fibrosis, called reversible hyperplasia. Bronchioloalveolar hyperplasia is characterized mainly by a focal increase in type II cells lining the interalveolar septa, called irreversible hyperplasia. Strong expression of napsin A in the alveolar walls in these hyperplastic lesions might suggest a tumorigenic potential with possible progression to adenoma and adenocarcinoma.