Apoptosis and Fas/Fas ligand mRNA expression in acute immune complex alveolitis in mice

Nomoto, Yoshitsugu; Kuwano, Koichi; Hagimoto, Naoki; Kunitake, Ritsuko; Kawasaki, Masayuki; Hara, Nobuyuki

doi:10.1183/09031936.97.10102351

Cited by 22 publications

(15 citation statements)

References 29 publications

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“…It is tempting to speculate that more prolonged Fas activation in premature lungs may contribute to the increased alveolar epithelial apoptosis described in early bronchopulmonary dysplasia. Analogously, the Fas/FasL system has been implicated as a critical mediator of type II cell apoptosis in clinical and experimental adult lung injury models that are characterized by epithelial damage and alveolar epithelial type II cell apoptosis (4,18,19,25,26,29,30,34).…”

Section: Discussionmentioning

confidence: 99%

Fas/FasL-mediated apoptosis in perinatal murine lungs

Paepe¹,

Mao²,

Embree-Ku³

et al. 2004

American Journal of Physiology-Lung Cellular and Molecular Phys

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I. Luks. Fas/FasL-mediated apoptosis in perinatal murine lungs. Am J Physiol Lung Cell Mol Physiol 287: L730 -L742, 2004; 10.1152/ajplung.00120.2004.-Postcanalicular lung development is characterized by a time-specific increase in alveolar epithelial type II cell apoptosis. We have previously demonstrated that, in fetal rabbits, developmental type II cell apoptosis coincides with transient upregulation of the cell death regulator Fas ligand (FasL). The aims of this study were 1) to determine the spatiotemporal patterns of pulmonary apoptosis and Fas/FasL gene expression in the murine model [embryonic day 17 (E17) through postnatal day 5 (P5)], and 2) to investigate the functional involvement of the Fas/FasL system by determining the effect of Fas activation and inhibition on perinatal pulmonary apoptosis. The apoptotic activity of alveolar epithelial type II cells, determined by combined TUNEL labeling and anti-surfactant protein B immunohistochemistry, showed a dramatic increase during the perinatal transition (type II cell apoptotic index Ͻ0.1% at E17, 1.5% at P1-P3, and 0.3% at P5). This timing of enhanced type II cell apoptosis coincided with a robust 14-fold increase in Fas mRNA and protein levels and a threefold increase in FasL protein levels; both Fas and FasL immunolocalized to type II and bronchial epithelial cells. In vitro and in vivo exposure of fetal and postnatal murine type II cells to anti-Fas antibody induced a fourfold increase in apoptotic activity that was prevented by administration of a broad-spectrum caspase inhibitor; the pulmonary apoptotic activity of Fas-deficient lpr mice remained unchanged. Conversely, administration of a caspase inhibitor to newborn mice (P1) resulted in marked diminution of pulmonary apoptotic activity. These combined findings strongly implicate the Fas/FasL system as a critical regulator of perinatal type II cell apoptosis. The developmental time dependence of apoptosis-related events in the murine model should facilitate investigations of the regulation of perinatal pulmonary apoptotic gene expression.programmed cell death; lpr; CD95; lung development DURING PERINATAL development, the distal lung parenchyma undergoes a series of orchestrated morphological and functional changes required for optimizing postnatal gas exchange. This process is initiated in utero during the transition from the pseudoglandular to the canalicular and saccular stages of lung development and is completed after birth during the alveolar stage. Postcanalicular lung development is characterized by a coordinated thinning of the interstitium, expansion of the alveolar septa, and a significant reduction in the number of alveolar type II cells (6,22).The loss of alveolar type II cells in postcanalicular lungs traditionally has been attributed to terminal differentiation of type II cells into type I cells, but recent observations suggest that apoptosis (programmed cell death) may be an important contributor to perinatal type II cell homeostasis as well (reviewed in Ref. 14). We previously demon...

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Section: Discussionmentioning

confidence: 99%

Fas/FasL-mediated apoptosis in perinatal murine lungs

Paepe¹,

Mao²,

Embree-Ku³

et al. 2004

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…The induction of apoptosis has been shown to be associated with various lung disorders including acute lung injury (Bardales et al, 1996), diffuse alveolar damage (Guinee et al, 1996), and idiopathic pulmonary fibrosis (Kuwano et al, 1996(Kuwano et al, , 1999a (Kuwano et al, 1999b(Kuwano et al, , 2000, silica (Iyer et al, 1996), immune complexes (Nomoto et al, 1997), and endotoxin (Cox et al, 1995) have also been shown to induce lung cell apoptosis directly. Repair after lung injury requires the elimination of inflammatory and unwanted cells from the tissue through phagocytosis (Polnovsky et al, 1993).…”

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confidence: 97%

Potential role of apoptotic macrophages in pulmonary inflammation and fibrosis

Wang

Antonini

Rojanasakul

et al. 2002

Journal Cellular Physiology

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Induction of apoptosis has been associated with a variety of exposures which result in inflammatory and fibrotic lung disorders. Macrophages are key regulatory cells in the lung; however, the role of apoptotic macrophages in those pulmonary disorders is not well characterized. In the present investigation, apoptotic macrophages were instilled into the lungs of rats to study directly the pulmonary responses to apoptotic cells. The effects of apoptotic macrophages on lung inflammation and fibrosis, as well as associated protein expression of TNF-alpha, TGF-beta, and matrix metalloproteinases (MMPs) were examined. Induction of macrophage apoptosis was carried out in vitro using a variety of known apoptosis inducers. Intratracheal administration of apoptotic macrophages (5 x 10(6) cells/rat) into the lung of rats caused an increase in pulmonary infiltration of macrophages and lung cell apoptosis 4 weeks after the treatment as indicated by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) assay. In contrast, pulmonary instillation of saline or normal control macrophages had no effect. Histological analysis of lung sections showed collagen deposition and fibrotic lesions after apoptotic cell treatment but not in control groups. Immunohistochemical studies revealed increased expression of TNF-alpha, TGF-beta, MMP2, and MMP9 in the treatment group 4 weeks after the treatment. These results suggest a role for macrophage apoptosis in the initiation of these lung disorders. This study provides direct evidence that apoptotic macrophages can induce lung inflammation and fibrosis and that this induction may be associated with increased expression of TNF-alpha, TGF-beta, MMP2, and MMP9. Published 2002 Wiley-Liss, Inc.

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“…Finally, the Fas/ FasL system has been implicated as critical regulator of alveolar type II cell apoptosis in physiological alveolar remodeling 10,11 and in various clinical and experimental models of adult lung injury. [23][24][25][26][27][28][29][30][31][32][33] It is therefore conceivable that Fas/FasL signaling may play an important role in BPD-associated apoptosis as well.…”

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confidence: 99%

Fas-Ligand-Induced Apoptosis of Respiratory Epithelial Cells Causes Disruption of Postcanalicular Alveolar Development

Paepe

Gundavarapu

Tantravahi

et al. 2008

The American Journal of Pathology

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Premature infants are at risk for bronchopulmonary dysplasia, a complex condition characterized by impaired alveolar development and increased alveolar epithelial apoptosis. The functional involvement of pulmonary apoptosis in bronchopulmonary dysplasiaassociated alveolar disruption remains undetermined. The aims of this study were to generate conditional lung-specific Fas-ligand (FasL) transgenic mice and to determine the effects of FasL-induced respiratory epithelial apoptosis on alveolar remodeling in postcanalicular lungs. Transgenic (TetOp) 7 -FasL responder mice, generated by pronuclear microinjection, were bred with Clara cell secretory protein (CCSP)-rtTA activator mice. Doxycycline (Dox) was administered from embryonal day 14 to postnatal day 7, and lungs were studied between embryonal day 19 and postnatal day 21. Dox administration induced marked respiratory epithelium-specific FasL mRNA and protein up-regulation in double-transgenic CCSP-rtTA

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Apoptosis and Fas/Fas ligand mRNA expression in acute immune complex alveolitis in mice

Abstract: These results suggest that apoptosis may be associated with the resolution of inflammation and with tissue repair and also suggest the involvement of the Fas antigen/Fas ligand pathway in acute immune complex alveolitis in mice.

Cited by 22 publications

References 29 publications

Fas/FasL-mediated apoptosis in perinatal murine lungs

Fas/FasL-mediated apoptosis in perinatal murine lungs

Potential role of apoptotic macrophages in pulmonary inflammation and fibrosis

Fas-Ligand-Induced Apoptosis of Respiratory Epithelial Cells Causes Disruption of Postcanalicular Alveolar Development

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