Alveolar Macrophage Dysregulation in Hermansky-Pudlak Syndrome Type 1

Rouhani, Farshid N.; Brantly, Mark; Markello, Thomas C.; Helip-Wooley, Amanda; O’Brien, Kevin; Hess, Richard A.; Huizing, Marjan; Gahl, William A.; Gochuico, Bernadette R.

doi:10.1164/rccm.200901-0023oc

Cited by 64 publications

(79 citation statements)

References 52 publications

(62 reference statements)

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“…Furthermore, alveolar inflammation precedes lung remodeling, consisting of both airspace enlargement and subsequent collagen deposition (8). Our longitudinal survey demonstrated that alveolitis began much earlier than previously suggested by BAL studies in both HPS mouse models carrying single mutations, and adult patients with HPS1 (14,34,35). These data provide strong support for a more comprehensive evaluation of the pediatric HPS population, and suggest that earlier treatment protocols (before the development of clinically apparent restrictive lung disease) may be important in modifying the disease course.…”

Section: Discussionmentioning

confidence: 50%

“…As previously described (14), subjects with HPS1 and healthy research volunteers were evaluated at the National Institutes of Health Clinical Center (Bethesda, MD) and were enrolled in protocols 95-HG-0193 and/ or 04-H-0211, which were approved by the Institutional Review Boards of the National Human Genome Research Institute (Bethesda, MD).…”

Section: Samples and Data From Patients With Hpsmentioning

confidence: 99%

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Early Alveolar Epithelial Dysfunction Promotes Lung Inflammation in a Mouse Model of Hermansky-Pudlak Syndrome

Atochina‐Vasserman

Bates

Zhang

et al. 2011

Am J Respir Crit Care Med

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Rationale: The pulmonary phenotype of Hermansky-Pudlak syndrome (HPS) in adults includes foamy alveolar type 2 cells, inflammation, and lung remodeling, but there is no information about ontogeny or early disease mediators. Objectives: To establish the ontogeny of HPS lung disease in an animal model, examine disease mediators, and relate them to patients with HPS1. Methods: Mice with mutations in both HPS1/pale ear and HPS2/ AP3B1/pearl (EPPE mice) were studied longitudinally. Total lung homogenate, lung tissue sections, and bronchoalveolar lavage (BAL) were examined for phospholipid, collagen, histology, cell counts, chemokines, surfactant protein D (SP-D), and S-nitrosylated SP-D. Isolated alveolar epithelial cells were examined for expression of inflammatory mediators, and chemotaxis assays were used to assess their importance. Pulmonary function test results and BAL from patients with HPS1 and normal volunteers were examined for clinical correlation. Measurements and Main Results: EPPE mice develop increased total lung phospholipid, followed by a macrophage-predominant pulmonary inflammation, and lung remodeling including fibrosis.

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Section: Discussionmentioning

confidence: 50%

Section: Samples and Data From Patients With Hpsmentioning

confidence: 99%

Early Alveolar Epithelial Dysfunction Promotes Lung Inflammation in a Mouse Model of Hermansky-Pudlak Syndrome

Atochina‐Vasserman

Bates

Zhang

et al. 2011

Am J Respir Crit Care Med

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“…First, there is strong evidence that macrophage-mediated inflammation precedes pulmonary fibrosis in patients with HPS. Bronchoalveolar lavage fluid of patients with HPS-PF contained increased total cell counts and alveolar macrophages (35), at a time when patients still had relatively preserved lung function. Furthermore, alveolar macrophages from patients with HPS have been shown to be constitutively activated, expressing excess cytokines and chemokines when studied ex vivo (35).…”

Section: Pulmonary Fibrosis: Pathogenesismentioning

confidence: 94%

“…Interestingly, ex vivo, pirfenidone showed significantly decreased inflammatory cytokines in the alveolar macrophages of patients with HPS (35). An initial clinical trial of pirfenidone in patients with HPS-1 showed no significant slowing of fibrosis progression by serial measurement of FVC (32).…”

Section: Clinical Management Of Pulmonary Fibrosismentioning

confidence: 98%

“…Bronchoalveolar lavage fluid from patients with HPS contains elevated levels of several cytokines, including chemokine (C-C motif) ligand 2 (CCL2/monocyte chemotactic protein [MCP]-1), macrophage colony-stimulating factor (M-CSF), and granulocyte-macrophage colonystimulating factor (GM-CSF) (35). Interestingly, elevation of CCL2 levels was directly associated with the progression of HPS-PF; a similar association has been observed in IPF and animal models of pulmonary fibrosis (36,37).…”

Section: Pulmonary Fibrosis: Pathogenesismentioning

confidence: 99%

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Pulmonary Fibrosis in Hermansky-Pudlak Syndrome

et al. 2016

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Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive genetic disorder characterized by oculocutaneous albinism and a bleeding diathesis due to platelet dysfunction. More than 50% of cases worldwide are diagnosed on the Caribbean island of Puerto Rico. Genetic testing plays a growing role in diagnosis; however, not all patients with HPS have identified genetic mutations. In Puerto Rico, patients with HPS are often identified shortly after birth by their albinism, although the degree of hypopigmentation is highly variable. Ten subtypes have been described. Patients with HPS-1, HPS-2, and HPS-4 tend to develop pulmonary fibrosis in Puerto Rico; 100% of patients with HPS-1 develop HPS-PF. HPS-PF and idiopathic pulmonary fibrosis are considered similar entities (albeit with distinct causes) because both can show similar histological disease patterns. However, in contrast to idiopathic pulmonary fibrosis, HPS-PF manifests much earlier, often at 30-40 years of age. The progression of HPS-PF is characterized by the development of dyspnea and increasingly debilitating hypoxemia. No therapeutic interventions are currently approved by the U.S. Food and Drug Administration for the treatment of HPS and HPS-PF. However, the approval of two new antifibrotic drugs, pirfenidone and nintedanib, has prompted new interest in identifying drugs capable of reversing or halting the progression of HPS-PF. Thus, lung transplantation remains the only potentially life-prolonging treatment. At present, two clinical trials are recruiting patients with HPS-PF to identify biomarkers for disease progression. Advances in the diagnosis and management of these patients will require the establishment of multidisciplinary centers of excellence staffed by experts in this disease.

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Molecular Genetics of Hermansky–Pudlak Syndrome

Cullinane

Huizing

Gahl

2013

Encyclopedia of Life Sciences

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Hermansky–Pudlak syndrome (HPS) is an autosomal recessive, genetically heterogeneous disorder characterised by oculocutaneous albinism and a bleeding diathesis. Subtype specific features such as neutropenic immunodeficiency and fatal lung fibrosis also occur. To date, nine human HPS subtypes (HPS‐1 to HPS‐9) and their associated genes have been identified. All of the HPS protein products are involved in biogenesis of lysosome‐related organelles (LROs) in specialised cells, including melanosomes in melanocytes and delta granules in platelets. The HPS proteins are all components of one of three biogenesis of lysosome‐related organelles complexes (BLOC‐1, BLOC‐2 or BLOC‐3) or the adaptor protein complex‐3. These complexes are essential for the correct formation of LROs, which are produced by the complex interaction of proteins, membranes and vesicles from the endocytic and biosynthetic pathways. Cells from patients with LRO disorders serve as useful tools for elucidating the complex pathways involved in the biogenesis of these organelles. Key Concepts: HPS is caused by mutations in nine known genes and is characterised by oculocutaneous albinism and a bleeding tendency. The proteins that are encoded by the HPS genes are all required for the correct formation of lysosome‐related organelles (LROs). LROs share features with lysosomes but have distinct morphology, composition and/or functions. LROs are maintained by the regulated flow of proteins, membranes and vesicles among the complex endosomal machinery. Novel players of LRO biogenesis are revealed by human disease and animal mutations, which continue to provide invaluable resources for elucidating the complex pathways involved in the biogenesis of these organelles.

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Alveolar Macrophage Dysregulation in Hermansky-Pudlak Syndrome Type 1

Abstract: 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.

Cited by 64 publications

References 52 publications

Early Alveolar Epithelial Dysfunction Promotes Lung Inflammation in a Mouse Model of Hermansky-Pudlak Syndrome

Early Alveolar Epithelial Dysfunction Promotes Lung Inflammation in a Mouse Model of Hermansky-Pudlak Syndrome

Pulmonary Fibrosis in Hermansky-Pudlak Syndrome

Molecular Genetics of Hermansky–Pudlak Syndrome

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