Histochem Cell Biol (2010) 134:205–213 DOI 10.1007/s00418-010-0724-8 O R I G I N A L P A P E R Histochemical and cellular changes accompanying the appearance of lung Wbrosis in an experimental mouse model for Hermansky Pudlak syndrome Lingyan Wang · Timothy Lyerla Accepted: 24 June 2010 / Published online: 7 July 2010 © The Author(s) 2010. This article is published with open access at Springerlink.com Abstract Hermansky Pudlak syndrome (HPS) is a hetero- geneous recessive genetic disease with a tendency to develop lung Wbrosis with aging. A mouse strain with two mutant HPS genes aVecting separate vesicle traYcking pathways, C57BL/6-Hps1ep-Ap3b1pe, exhibits severe lung abnormalities at young ages, including enlarged alveolar type II (ATII) cells with giant lamellar bodies and foamy alveolar macrophages (AMs), which are readily identiWed histologically. In this study, the appearance of lung Wbrosis in older animals was studied using classical histological and biochemical methods. The HPS double mutant mice, but not Chediak Higashi syndrome (C57BL/6-Lystbg-J-J, CHS) or C57BL/6J black control (WT) mice, were found to develop lung Wbrosis at about 17 months of age using Mas- son trichrome staining, which was conWrmed by hydroxy- proline analysis. TGF 1 levels were elevated in bronchial alveolar lavage samples at all ages tested in the double mutant, but not WT or CHS mice, indicative of a preWbrotic condition in this experimental strain; and AMs were highly positive for this cytokine using immunohistochemistry staining. Prosurfactant protein C staining for ATII cells showed redistribution and dysmorphism of these cells with aging, but there was no evidence for epithelial-mesenchy- mal transition of ATII cells by dual staining for prosurfac- tant C protein and -smooth muscle actin. This investigation showed that the HPS double mutant mouse strain develops interstitial pneumonia (HPSIP) past 1 year of age, which may be initiated by abnormal ATII cells and exacerbated by AM activation. With prominent preWbrotic L. Wang (&) · T. Lyerla Biology Department, Clark University, 950 Main Street, Worcester, MA 01610, USA e-mail: lwang@clarku.edu abnormalities, this double mutant may serve as a model for interventive therapy in HPS. Keywords Pulmonary Wbrosis · Hermansky Pudlak syndrome · Alveolar macrophages · Alveolar type II cells · TGF 1 Introduction Hermansky Pudlak syndrome (HPS) is a heterogeneous recessive genetic disease which aVects vesicle traYcking in lysosome-related organelles, including melanosomes, plate- let dense granules, and lamellar bodies in alveolar type II (ATII) cells (Bonifacino 2004; Wei 2006). Some patients with this disease develop pulmonary Wbrosis, also called HPS interstitial pneumonia (HPSIP, Nakatani et al. 2000). HPSIP is characterized by giant lamellar bodies of ATII cells and their apparent degeneration, which is hypothesized to play a major role in the development of this Wbrosing disorder. There are some 14 mouse mutants that are animal mod- els for HPS (Li et al. 2004). The mouse pale ear mutant, HPS1ep, is the model for the most common HPS disease, HPS 1, while the pearl mutant, Ap3b1pe, is the model for HPS 2. As for all HPS genes, the products HPS1 and HPS2 (a subunit of the AP-3 adaptor complex, Feng et al. 1999), respectively, are involved in vesicle traYcking and the secretory process, and known to inXuence separate path- ways (Feng et al. 2002). The HPS mouse strain, C57BL/ 6-Hps1ep-Ap3b1pe, combines two mutant HPS genes into one mouse model for HPS (Feng et al. 2002). Previous study of this strain showed that, at 1 year of age or younger, the lungs of these animals were Wlled with foamy and binucleate alveolar macrophages (AMs), exhibited emphysema, impaired lung ventilation, and giant lamellar 123