Epithelial-macrophage interactions determine pulmonary fibrosis susceptibility in Hermansky-Pudlak syndrome

Young, Lisa R.; Gulleman, Peter M.; Short, Chelsi W; Tanjore, Harikrishna; Sherrill, Taylor P.; Qi, Aidong; McBride, Andrew; Zaynagetdinov, Rinat; Benjamin, John T.; Lawson, William; Novitskiy, Sergey V.; Blackwell, Timothy S.

doi:10.1172/jci.insight.88947

Cited by 83 publications

(78 citation statements)

References 52 publications

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“…Bleomycin induced significantly greater increases in Ccl2 and Cxcl12 gene expression in WT mice than in Cnr1 -/-mice ( Figure 6B), and protein levels of MCP-1 and CXCL12 in lung were also dramatically attenuated in Cnr1 -/-mice ( Figure 6C), which implicates endocannabinoids acting via CB 1 R in promoting chemokine secretion. Furthermore, a recent study exemplified an interaction between ATII cells and alveolar macrophages in fibrogenesis: MCP-1 secretion is increased in ATII cells from mice with Hermansky-Pudlak lung fibrosis, which increases alveolar macrophages in the lung, resulting in increased TGF-β secretion (44). In the current study, bleomycin-induced Tgfb1 gene expression was attenuated both in Cnr1 -/-mice and following CB 1 R antagonist treatment.…”

Section: Discussionsupporting

confidence: 60%

Cannabinoid CB1 receptor overactivity contributes to the pathogenesis of idiopathic pulmonary fibrosis

Çınar¹,

Gochuico²,

Iyer³

et al. 2017

JCI Insight

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Section: Discussionsupporting

confidence: 60%

Cannabinoid CB1 receptor overactivity contributes to the pathogenesis of idiopathic pulmonary fibrosis

Çınar¹,

Gochuico²,

Iyer³

et al. 2017

JCI Insight

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“…The primary insult responsible for lung fibrosis appears to be defects in the biogenesis of lamellar bodies, which are LROs in alveolar type II (AT2) cells responsible for surfactant synthesis and secretion . Consequent inflammatory sequelae, which likely result from reduced surfactant levels, initiate and expand the fibrotic response . A subset of HPS1 and HPS4 patients also suffer from granulomatous colitis (a type of inflammatory bowel disease), the etiology of which is currently unknown.…”

Section: The Hermansky‐pudlak Syndromesmentioning

confidence: 99%

“…A long‐term consequence of this effect on AT2 cells in HPS1 and HPS4 patients is a progressive lung fibrosis that is typically lethal in the fifth decade of life . Modeling of the disease in double Hps1 / AP3b1 ‐deficient mice—and more recently in single Hps1 ‐ or Ap3b1 ‐deficient mice treated with bleomycin—indicates that the affected lung epithelium hypersecretes nitric oxide synthase and the chemokine MCP‐1 . Both of these factors activate alveolar macrophages to hypersecrete additional chemokines, inflammatory cytokines and TGFβ, all of which contribute to AT2 apoptosis and fibrotic macrophage infiltration .…”

Section: Hps‐associated Protein Complexesmentioning

confidence: 99%

The road to lysosome‐related organelles: Insights from Hermansky‐Pudlak syndrome and other rare diseases

Bowman

Bi‐Karchin

et al. 2019

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Lysosome-related organelles (LROs) comprise a diverse group of cell type-specific, membrane-bound subcellular organelles that derive at least in part from the endolysosomal system but that have unique contents, morphologies and functions to support specific physiological roles. They include: melanosomes that provide pigment to our eyes and skin; alpha and dense granules in platelets, and lytic granules in cytotoxic T cells and natural killer cells, which release effectors to regulate hemostasis and immunity; and distinct classes of lamellar bodies in lung epithelial cells and keratinocytes that support lung plasticity and skin lubrication. The formation, maturation and/or secretion of subsets of LROs are dysfunctional or entirely absent in a number of hereditary syndromic disorders, including in particular the Hermansky-Pudlak syndromes. This review provides a comprehensive overview of LROs in humans and model organisms and presents our current understanding of how the products of genes that are defective in heritable diseases impact their formation, motility and ultimate secretion.

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“…TGF-β is constitutively present in the lung interstitium in a latent form, and upon injury to the epithelium or endothelium, is converted from to an active form via a process that requires the αvβ6 integrin (33–37). Alternatively, active TGF-β can be released by macrophages, myofibroblasts or other cells including platelets (38, 39). Active TGF-β binds to one of a family of TGF-β receptors present on the cell surface, initiating an intracellular signaling cascade, which results in the phosphorylation of transcription factors referred to as small mothers against decapentaplegic (Smads).…”

Section: Tgf-β Oxidant Signaling and Fibrosismentioning

confidence: 99%

Reactive oxygen species as signaling molecules in the development of lung fibrosis

González-González

Chandel

Jain

et al. 2017

Translational Research

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Pulmonary fibrosis is a relatively rare but devastating disease characterized by the excessive deposition of extracellular matrix. The increased matrix results in reduced lung compliance and increased work of breathing, while the obliteration of alveolar-capillary structures can result in hypoxemia and pulmonary hypertension, which manifests clinically as worsening shortness of breath, respiratory failure and death. Unbiased genome wide association studies combined with animal models suggest that damage to the alveolar epithelium is the initiating factor in pulmonary fibrosis. This epithelial injury leads to the activation and proliferation of myofibroblasts that secrete extracellular matrix proteins characteristic of fibrosis. The best described molecular link between alveolar epithelial dysfunction and myofibroblast activation and proliferation is the profibrotic cytokine transforming growth factor-β (TGF-β). We and others have found that mitochondrial and NADPH oxidase-generated reactive oxygen species (ROS) play a signaling role to enhance TGF-β signaling and promote fibrosis. This purpose of this review is to review ROS signaling downstream of the activation of TGF-β. We suggest that an improved understanding of these pathways might explain the failure of nonselective antioxidants to improve outcomes in patients with pulmonary fibrosis and might identify novel targets for therapy.

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Epithelial-macrophage interactions determine pulmonary fibrosis susceptibility in Hermansky-Pudlak syndrome

Cited by 83 publications

References 52 publications

Cannabinoid CB1 receptor overactivity contributes to the pathogenesis of idiopathic pulmonary fibrosis

Cannabinoid CB1 receptor overactivity contributes to the pathogenesis of idiopathic pulmonary fibrosis

The road to lysosome‐related organelles: Insights from Hermansky‐Pudlak syndrome and other rare diseases

Reactive oxygen species as signaling molecules in the development of lung fibrosis

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