Restoration of PPARγ reverses lipid accumulation in alveolar macrophages of GM-CSF knockout mice

Malur, Anagha; Baker, Anna D.; McCoy, Almedia J.; Wells, Greg; Barna, Barbara P.; Kavuru, Mani S.; Thomassen, Mary Jane

doi:10.1152/ajplung.00128.2010

Cited by 45 publications

(41 citation statements)

References 39 publications

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“…By its action on alveolar macrophages it significantly contributes to surfactant homeostasis (149,166). Recently, several publications highlighted GM-CSF to be highly protective in different preclinical models of ALI, including K. pneumoniae infection, influenza virus pneumonia, LPS-induced lung injury, and others (190).…”

Section: Putative Candidates For Treatment Of Alimentioning

confidence: 99%

Novel concepts of acute lung injury and alveolar-capillary barrier dysfunction

Herold

Gabrielli

Vadász

2013

American Journal of Physiology-Lung Cellular and Molecular Phys

183

178

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Herold S, Gabrielli NM, Vadász I. Novel concepts of acute lung injury and alveolar-capillary barrier dysfunction. Am J Physiol Lung Cell Mol Physiol 305: L665-L681, 2013. First published September 13, 2013 doi:10.1152/ajplung.00232.2013In this review we summarize recent major advances in our understanding on the molecular mechanisms, mediators, and biomarkers of acute lung injury (ALI) and alveolar-capillary barrier dysfunction, highlighting the role of immune cells, inflammatory and noninflammatory signaling events, mechanical noxae, and the affected cellular and molecular entities and functions. Furthermore, we address novel aspects of resolution and repair of ALI, as well as putative candidates for treatment of ALI, including pharmacological and cellular therapeutic means. alveolar-capillary barrier dysfunction; molecular mechanism; pharmacological and cell-based therapy; pulmonary edema; zaacute lung injury/acute respiratory distress syndrome Immune Cells and Inflammatory Signaling Pathways in ALIOne of the central concepts in acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) is that an unbalanced quantity or quality of the inflammatory response aggravates epithelial or endothelial injury. This includes a dysregulated recruitment of leukocytes and/or an exaggerated activation of these cells; inappropriate expression of cytokines, lipid mediators, or reactive oxygen species; enhanced activation of death receptor signaling (97,98,140,207,240); or an uncontrolled activity of platelets or the coagulation cascade (154). In general, these responses are initiated and maintained by recognition of danger-or pathogen-associated molecular patterns

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Section: Putative Candidates For Treatment Of Alimentioning

confidence: 99%

Novel concepts of acute lung injury and alveolar-capillary barrier dysfunction

Herold

Gabrielli

Vadász

2013

American Journal of Physiology-Lung Cellular and Molecular Phys

183

178

View full text Add to dashboard Cite

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“…Nonetheless, a study has demonstrated that PPARg overexpression in GM-CSF-knockout lung macrophages, which are deficient in PPARg expression, rescues alveolar surfactant accumulation, indicating potential regulation of PPARg expression by GM-CSF signaling. 62 It is, therefore, possible that acquired downregulation of other GM-CSF signaling pathways may be involved in the pathogenesis. The association between increased IFN-g and reduced PPARg has been described.…”

Section: Blood 8 January 2015 X Volume 125 Number 2 Aberrant T Cellmentioning

confidence: 99%

T-cell–restricted T-bet overexpression induces aberrant hematopoiesis of myeloid cells and impairs function of macrophages in the lung

Iriguchi

Kikuchi

Kaneko

et al. 2015

Blood

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Key Points• Mice overexpressing T-bet in T cells show aberrant hematopoiesis of myeloid cells and functional conversion of regional macrophages.• The mice developed a severe PAP-like disease with a hematopoietic disorder resembling the human disease.Although overexpression of T-bet, a master transcription factor in type-1 helper T lymphocytes, has been reported in several hematologic and immune diseases, its role in their pathogenesis is not fully understood. In the present study, we used transgenic model mice (T-bet tg/wt and T-bet tg/tg ) to investigate the effects of T-bet overexpression selectively in T lymphocytes on the development of hematologic and immune diseases. The results showed that T-bet overexpression in T cells spontaneously induced maturation arrest in the mononuclear phagocyte lineage, as well as spontaneous dermatitis and pulmonary alveolar proteinosis (PAP)-like disease in T-bet tg/wt and T-bet tg/tg mice, respectively. T-bet tg/tg alveoli with the PAP phenotype showed remarkable reorganization of alveolar mononuclear phagocyte subpopulations and impaired function, in addition to augmented T-cell infiltration. In addition, PAP development in T-bet tg/tg mice was found to be associated with increased migration of myeloid cells from the bone marrow into the peripheral blood. These findings reveal an unexpected link between T-bet overexpression in T lymphocytes and the development of PAP caused by reorganization of mononuclear phagocytes in the lung, and provide new insight into the molecular pathogenesis of secondary PAP accompanied by hematologic disorders. (Blood. 2015;125(2):370-382)

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“…The AM accretion of lipid is attributed to compromised catabolic capacity (10) and affected signalling cascade(s) downstream of GM-CSF involving PPARγ have been extensively characterised (14,15). cells increases alveolar surfactant but leads to a neutral lipid accumulation in AT2 cells (17).…”

mentioning

confidence: 99%

Hepatic Steatosis Accompanies Pulmonary Alveolar Proteinosis

Hunt

Malur

Monfort

et al. 2017

Am J Respir Cell Mol Biol

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Maintenance of tissue-specific organ lipid compositions characterises mammalian lipid homeostasis. Lung and liver synthesise mixed phosphatidylcholine (PC) molecular species subsequently "tailored" for function. Lungs progressively enrich disaturated PC (DSPC) directed to lamellar body (LB) surfactant stores prior to secretion. Liver accumulates polyunsaturated PC directed to VLDL assembly and secretion, or triglyceride stores. In each tissue, selective PC species enrichment mechanisms lie at the heart of effective homeostasis. We tested potential coordination between these spatially separated, but possibly complementary phenomena under a major derangement of lung PC metabolism, Pulmonary Alveolar Proteinosis (PAP), which overwhelms homeostasis leading to excessive surfactant accumulation. Using static and dynamic lipidomics techniques we compared (i) tissue PC compositions and contents and (ii) in lungs, the absolute rates of synthesis from both control mice and the GM-CSF knockout model of PAP. Significant DSPC accumulation in BALF, Alveolar Macrophage (AM) and lavaged lung tissue occurred alongside increased PC synthesis consistent with reported defects in AM surfactant turnover. However, microscopy using oil red O staining, CARS, SHG and TEM also revealed neutral lipid droplet accumulations in alveolar lipofibroblasts of GM-CSF KO animals suggesting lipid homeostasis deficits extend beyond AMs. PAP plasma PC composition was significantly PUFA-enriched but content was unchanged and hepatic PUFA-enriched PC content increased by 50% with an accompanying micro/macrovesicular steatosis and a fibrotic damage pattern consistent with NAFLD. These data suggest a hepato-pulmonary axis of PC metabolism coordination with wider implications for understanding and managing lipid pathologies where compromise of one organ has unexpected consequences for another.

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Restoration of PPARγ reverses lipid accumulation in alveolar macrophages of GM-CSF knockout mice

Cited by 45 publications

References 39 publications

Novel concepts of acute lung injury and alveolar-capillary barrier dysfunction

Novel concepts of acute lung injury and alveolar-capillary barrier dysfunction

T-cell–restricted T-bet overexpression induces aberrant hematopoiesis of myeloid cells and impairs function of macrophages in the lung

Hepatic Steatosis Accompanies Pulmonary Alveolar Proteinosis

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