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. 2009 Dec 1;180(11):1114-21.
doi: 10.1164/rccm.200901-0023OC. Epub 2009 Sep 3.

Alveolar macrophage dysregulation in Hermansky-Pudlak syndrome type 1

Farshid N Rouhani  1 , Mark L Brantly, Thomas C Markello, Amanda Helip-Wooley, Kevin O'Brien, Richard Hess, Marjan Huizing, William A Gahl, Bernadette R Gochuico
Affiliations

Alveolar macrophage dysregulation in Hermansky-Pudlak syndrome type 1

Farshid N Rouhani et al. Am J Respir Crit Care Med. .

Abstract

Rationale: Individuals with Hermansky-Pudlak syndrome type 1 (HPS-1), an autosomal recessive disorder characterized by defective biogenesis of lysosome-related organelles, develop an accelerated form of progressive fibrotic lung disease. The etiology of pulmonary fibrosis associated with HPS-1 is unknown.

Objectives: To investigate the potential pathogenesis of pulmonary fibrosis in HPS-1, lung cells and proteins from individuals with HPS-1 were studied.

Methods: Forty-one subjects with HPS-1 with and without pulmonary fibrosis were evaluated with pulmonary function tests, high-resolution computed tomography scan, and bronchoscopy. Bronchoalveolar lavage cells and analytes were analyzed.

Measurements and main results: Concentrations of total bronchoalveolar lavage cells and alveolar macrophages were significantly higher in epithelial lining fluid from subjects with HPS-1 with and without pulmonary fibrosis compared with healthy research volunteers. Concentrations of cytokines and chemokines (i.e., monocyte chemoattractant protein-1, macrophage inflammatory protein-1alpha, and granulocyte-macrophage colony-stimulating factor) in alveolar epithelial lining fluid were significantly higher in subjects with HPS-1 with and without pulmonary fibrosis compared with healthy research volunteers (P < 0.001). In vitro, HPS-1 pulmonary fibrosis alveolar macrophages, which did not express HPS1 mRNA, secreted significantly higher concentrations of monocyte chemoattractant protein-1, macrophage inflammatory protein-1alpha, and regulated upon activation, normal T cell expressed and secreted (RANTES) protein compared with normal cells (P = 0.001, P = 0.014, and P = 0.011, respectively). Pirfenidone suppressed HPS-1 alveolar macrophage cytokine and chemokine secretion in vitro in a dose-dependent manner.

Conclusions: In HPS-1, alveolar inflammation predominantly involves macrophages and is associated with high lung concentrations of cytokines and chemokines. HPS-1 alveolar macrophages provide a model system in which to study the pathogenesis and treatment of HPS pulmonary fibrosis.

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Figures

Figure 1.
Figure 1.
(A–D) High-resolution computed tomography (HRCT) scan findings in subjects with Hermansky-Pudlak syndrome type 1 (HPS-1) pulmonary fibrosis. Representative HRCT scan images from four individual subjects with HPS-1 pulmonary fibrosis are shown. Reticulation (arrowheads), honeycombing (arrows), and ground glass opacification (open arrows) are found in subjects with HPS-1 pulmonary fibrosis.
Figure 2.
Figure 2.
Increased alveolar concentrations of total cells and alveolar macrophages (AMs) in subjects with Hermansky-Pudlak syndrome type 1 (HPS-1). (A–C) Concentrations of total cells in bronchoalveolar lavage (BAL) fluid (× 103 cells/ml) and alveolar epithelial lining fluid (ELF) (× 106 cells/ml) were significantly higher in subjects with HPS-1 (HPS) and HPS-1 pulmonary fibrosis (HPSPF) compared with healthy research volunteers (NV). In ELF, concentrations (× 106 cells/ml) of AMs were significantly higher in subjects with HPS-1 and HPSPF compared with NV subjects. Subjects with HPS-1 had significantly higher concentrations of BAL cells and AMs in ELF compared with subjects with HPSPF. (D) No significant differences were found in peripheral blood concentrations of total leukocytes (WBC) or percentage of monocytes (mono) in subjects with HPS-1 (solid columns) and those with HPSPF (open columns).
Figure 3.
Figure 3.
High alveolar concentrations of cytokines and chemokines in subjects with Hermansky-Pudlak syndrome type 1 (HPS-1) with and without pulmonary fibrosis. Concentrations (pg/ml) of monocyte chemoattractant protein (MCP)-1, macrophage inflammatory protein-1α (MIP-1a), granulocyte-macrophage colony-stimulating factor (GM-CSF), and macrophage colony-stimulating factor (M-CSF) were significantly higher in alveolar epithelial lining fluid (ELF) from subjects with HPS-1 pulmonary fibrosis (HPSPF) compared with healthy research volunteers (NV), and concentrations of MCP-1, MIP-1α, and GM-CSF were significantly higher from subjects with HPS-1 (HPS) compared with NV subjects. Subjects with HPSPF had significantly higher concentrations of MCP-1, GM-CSF, and M-CSF compared with subjects with HPS-1.
Figure 4.
Figure 4.
Cellular expression of HPS1 in healthy research volunteers, but not in subjects with Hermansky-Pudlak syndrome type 1 (HPS-1). (A) Northern blot analysis revealed that alveolar macrophages (AM) and fibroblasts from healthy research volunteers (NV), and not alveolar macrophages from subjects with HPS-1, express HPS1 mRNA. (B) Amplification of cDNA by reverse transcriptase-polymerase chain reaction (RT-PCR) using primers for HPS1 demonstrated that a 414-base pair (bp) HPS1 PCR product is expressed in peripheral blood mononuclear cells (PBMCs) and alveolar macrophages (AM) from two representative healthy volunteers (NV1 and NV2), but not in PBMCs from a representative subject with HPS-1. A 353-bp RT-PCR product was generated using primers for human β-actin.
Figure 5.
Figure 5.
Cytokine secretion by Hermansky-Pudlak syndrome type 1 (HPS-1) and normal cultured alveolar macrophages and suppression by pirfenidone in HPS-1 cells. (A) Concentrations (pg/ml) of monocyte chemoattractant protein (MCP)-1, macrophage inflammatory protein-1α (MIP-1a), and regulated upon activation, normal T cell expressed and secreted (RANTES) were significantly higher in conditioned medium from alveolar macrophages cultured for 24 hours from subjects with HPS-1 pulmonary fibrosis (HPSPF) (n = 18) compared with healthy research volunteers (NV) (n = 6). (B) Concentrations of MIP-1α, MCP-1, RANTES, macrophage colony-stimulating factor (M-CSF), macrophage inflammatory protein (MIP)-4, and IFN-γ (IFNg), but not granulocyte-macrophage colony-stimulating factor (GM-CSF) or IL12p40, in conditioned medium from alveolar macrophages from subjects with HPS-1 pulmonary fibrosis (n = 6) cultured for 24 hours were lower with increasing concentrations of pirfenidone.
Figure 5.
Figure 5.
Cytokine secretion by Hermansky-Pudlak syndrome type 1 (HPS-1) and normal cultured alveolar macrophages and suppression by pirfenidone in HPS-1 cells. (A) Concentrations (pg/ml) of monocyte chemoattractant protein (MCP)-1, macrophage inflammatory protein-1α (MIP-1a), and regulated upon activation, normal T cell expressed and secreted (RANTES) were significantly higher in conditioned medium from alveolar macrophages cultured for 24 hours from subjects with HPS-1 pulmonary fibrosis (HPSPF) (n = 18) compared with healthy research volunteers (NV) (n = 6). (B) Concentrations of MIP-1α, MCP-1, RANTES, macrophage colony-stimulating factor (M-CSF), macrophage inflammatory protein (MIP)-4, and IFN-γ (IFNg), but not granulocyte-macrophage colony-stimulating factor (GM-CSF) or IL12p40, in conditioned medium from alveolar macrophages from subjects with HPS-1 pulmonary fibrosis (n = 6) cultured for 24 hours were lower with increasing concentrations of pirfenidone.
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