Pulmonary alveolar proteinosis in SCID mice.

Jennings, Veronica M.; Dillehay, Dirck L.; Webb, Susana; Brown, Lou Ann S.

doi:10.1165/ajrcmb.13.3.7654386

Cited by 25 publications

(9 citation statements)

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“…37 One showed the development of secondary PAP in scid/scid mice, presumably recapitulating secondary PAP patients with immunodeficiency, although the mechanism has not yet been identified. 38 In the present model, it is clearly indicated that secondary PAP developed under aberrant T-cell activation by T-bet with monocytosis. On the basis of this finding, we suggest that T-bet-overexpressing T cells act to initiate the pathogenesis of secondary PAP.…”

Section: Discussionmentioning

confidence: 51%

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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Section: Discussionmentioning

confidence: 51%

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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“…Animal models of increased surfactant phospholipid and increased SP pool sizes include silica and mineral dust exposure (4), the severe-combined immunodeficient mouse (16), gene-targeted disruption of the GM-CSF or GM-CSF receptor ␤/C gene (13,26), and overexpression of IL-4 (10). Increased surfactant phospholipid in SP-D(Ϫ/Ϫ) mice was not associated with increased amounts of SPs, distinguishing this phenotype from the alveolar lipoproteinosis syndromes.…”

Section: Discussionmentioning

confidence: 99%

Surfactant metabolism in SP-D gene-targeted mice

Ikegami

Whitsett

Jobe

et al. 2000

American Journal of Physiology-Lung Cellular and Molecular Phys

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Mice with surfactant protein (SP)-D deficiency have three to four times more surfactant lipids in air spaces and lung tissue than control mice. We measured multiple aspects of surfactant metabolism and function to identify abnormalities resulting from SP-D deficiency. Relative to saturated phosphatidylcholine (Sat PC), SP-A and SP-C were decreased in the alveolar surfactant and the large-aggregate surfactant fraction. Although large-aggregate surfactant from SP-D gene-targeted [(-/-)] mice converted to small-aggregate surfactant more rapidly, surface tension values were comparable to values for surfactant from SP-D wild-type [(+/+)] mice. (125)I-SP-D was cleared with a half-life of 7 h from SP-D(-/-) mice vs. 13 h in SP-D(+/+) mice. Although initial incorporation and secretion rates for [(3)H]palmitic acid and [(14)C]choline into Sat PC were similar, the labeled Sat PC was lost from the lungs of SP-D(+/+) mice more rapidly than from SP-D(-/-) mice. Clearance rates of intratracheal [(3)H]dipalmitoylphosphatidylcholine were used to estimate net clearances of Sat PC, which were approximately threefold higher for alveolar and total lung Sat PC in SP-D(-/-) mice than in SP-D(+/+) mice. SP-D deficiency results in multiple abnormalities in surfactant forms and metabolism that cannot be attributed to a single mechanism.

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“…Rats exposed to inhaled silica develop PAP [90] although the mechanism was not determined. PAP also develops in mice with severe combined immunodeficiency, again without determination of the mechanism involved [91]. A recent study reported that use of dichloromethylene diphosphonic acid-encapsulated liposomes to reduce alveolar macrophage numbers increased pulmonary surfactant levels [92].…”

Section: Pathogenesis Of Secondary Papmentioning

confidence: 99%

The molecular basis of pulmonary alveolar proteinosis

Carey¹,

Trapnell²

2010

Clinical Immunology

206

190

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Pulmonary alveolar proteinosis (PAP) comprises a heterogenous group of diseases characterized by abnormal surfactant accumulation resulting in respiratory insufficiency, and defects in alveolar macrophage-and neutrophil-mediated host defense. Basic, clinical and translational research over the past two decades have raised PAP from obscurity, identifying the molecular pathogenesis in over 90% of cases as a spectrum of diseases involving the disruption of GM-CSF signaling. Autoimmune PAP represents the vast majority of cases and is caused by neutralizing GM-CSF autoantibodies. Genetic mutations that disrupt GM-CSF receptor signaling comprise a rare form of hereditary PAP. In both autoimmune and hereditary PAP, loss of GM-CSF signaling blocks the terminal differentiation of alveolar macrophages in the lungs impairing the ability of alveolar macrophages to catabolize surfactant and to perform many host defense functions. Secondary PAP occurs in a variety of clinical diseases that presumedly cause the syndrome by reducing the numbers or functions of alveolar macrophages, thereby impairing alveolar macrophage-mediated pulmonary surfactant clearance. A similar phenotype occurs in mice deficient in the production of GM-CSF or GM-CSF receptors. PAP and related research has uncovered a critical and emerging role for GM-CSF in the regulation of pulmonary surfactant homeostasis, lung host defense, and systemic immunity.

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Pulmonary alveolar proteinosis in SCID mice.

Cited by 25 publications

References 0 publications

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

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

Surfactant metabolism in SP-D gene-targeted mice

The molecular basis of pulmonary alveolar proteinosis

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