Essential roles of the Fas-Fas ligand pathway in the development of pulmonary fibrosis

Kuwano, Kazuyoshi; Hagimoto, Naoki; Kawasaki, Masayuki; Yatomi, Takehiro; Nakamura, Norio; Nagata, Shinji; Suda, Takafumi; Kunitake, Ritsuko; Maeyama, Takashige; Miyazaki, Hiroyuki; Hara, Nobuyuki

doi:10.1172/jci5628

Cited by 326 publications

(238 citation statements)

References 32 publications

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“…), but we did not observe any evidence for T cell activation or any significant activation of apoptotic pathways. Although in animal models of pulmonary fibrosis the fibrotic response may depend on intact tumor necrosis factor ␣ or Fas signaling pathways (31)(32)(33)(34)(35), activation of these pathways was not apparent in this study.…”

Section: Discussionmentioning

confidence: 67%

Gene expression analysis reveals matrilysin as a key regulator of pulmonary fibrosis in mice and humans

Zuo

Kaminski

Eugui

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

550

487

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Pulmonary fibrosis is a progressive and largely untreatable group of disorders that affects up to 100,000 people on any given day in the United States. To elucidate the molecular mechanisms that lead to end-stage human pulmonary fibrosis we analyzed samples from patients with histologically proven pulmonary fibrosis (usual interstitial pneumonia) by using oligonucleotide microarrays. Gene expression patterns clearly distinguished normal from fibrotic lungs. Many of the genes that were significantly increased in fibrotic lungs encoded proteins associated with extracellular matrix formation and degradation and proteins expressed in smooth muscle. Using a combined set of scoring systems we determined that matrilysin (matrix metalloproteinase 7), a metalloprotease not previously associated with pulmonary fibrosis, was the most informative increased gene in our data set. Immunohistochemisry demonstrated increased expression of matrilysin protein in fibrotic lungs. Furthermore, matrilysin knockout mice were dramatically protected from pulmonary fibrosis in response to intratracheal bleomycin. Our results identify matrilysin as a mediator of pulmonary fibrosis and a potential therapeutic target. They also illustrate the power of global gene expression analysis of human tissue samples to identify molecular pathways involved in clinical disease.usual interstitial pneumonia ͉ microarray analysis ͉ informative genes ͉ bleomycin ͉ matrix metalloproteases

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Section: Discussionmentioning

confidence: 67%

Gene expression analysis reveals matrilysin as a key regulator of pulmonary fibrosis in mice and humans

Zuo

Kaminski

Eugui

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

550

487

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“…Bleomycin induces the expression of TNF receptors in mice (22). In an in vivo study, Fas-and FasLdeficient C3H mice (lpr/lpr and gld/gld) displayed reduced susceptibility to bleomycin-induced pulmonary fibrosis (16). However, in a subsequent study, Aoshiba et al (3) used lpr/lpr and gld/gld in the C57BL/6 murine strain and found no change in bleomycin-induced pulmonary fibrosis.…”

Section: Discussionmentioning

confidence: 99%

“…Several studies have suggested that the extrinsic apoptotic pathway is essential in bleomycin model for lung injury and fibrosis (11,16). Bleomycin induces the expression of TNF receptors in mice (22).…”

Section: Discussionmentioning

confidence: 99%

“…In vivo, excessive apoptosis of pulmonary cells has been correlated with bleomycin-induced upregulation of Fas and Fas ligand (FasL) in murine models of pulmonary fibrosis (12,16). However, cell culture experiments using primary rat lung epithelial cells and transformed mouse lung epithelial (MLE) cells provided evidence for activation of the intrinsic pathway of apoptosis by bleomycin in a c-Jun NH 2 -terminal kinase-(JNK) dependent manner (17).…”

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confidence: 99%

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Bleomycin induces the extrinsic apoptotic pathway in pulmonary endothelial cells

Mungunsukh

Griffin

Lee

et al. 2010

American Journal of Physiology-Lung Cellular and Molecular Phys

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Bleomycin, a chemotherapeutic agent, can cause pulmonary fibrosis in humans and is commonly used to induce experimental pulmonary fibrosis in rodents. In cell culture, bleomycin causes single- and double-stranded DNA breaks and produces reactive oxidative species, both of which require iron (Fe2+) and O2. The mechanism of bleomycin-induced apoptosis is controversial due to its complexity. We investigated bleomycin apoptotic signaling events in primary pulmonary endothelial cells. Time course experiments revealed that bleomycin induced apoptosis within 4 h. Caspase-8, the initiator caspase for the extrinsic pathway, was activated within 2 h and preceded activation of the effector caspases-3 and -6 (4 h). Caspase-9, the initiator of the intrinsic pathway and release of cytochrome c from the mitochondria were not detected at these time points. Bleomycin induced the expression of Bcl-2 and Bcl-xL, Bcl-2 family member proteins that protect cells from the mitochondria-dependent intrinsic apoptosis. Real-time quantitative RT-PCR results demonstrated that, at 4–8 h, bleomycin induced expression of TNF and TNF receptor family genes known to induce the extrinsic apoptotic pathway. Silencing of the death receptor adaptor protein Fas-associated death domain by short interfering RNA significantly reduced bleomycin-induced apoptosis. Apoptosis was also abrogated by caspase-8 inhibition, but only slightly reduced by caspase-3 inhibition. Together, these data suggest that bleomycin initiates apoptosis via the extrinsic pathway.

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“…Abnormalities in the regulation of apoptosis have been associated with several pulmonary diseases, including acute lung injury, 11,12 diffuse alveolar damage, 13 idiopathic pulmonary fibrosis, 14 and lung disorders caused by bleomycin, 15,16 silica, 17 endotoxin, 18 and the deposition of immune complexes. 19 Despite growing evidence for a role of apoptosis and lung surfactant in pulmonary disorders, the relationship between these two events is not well understood.…”

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confidence: 99%

Role of lung surfactant in phagocytic clearance of apoptotic cells by macrophages in rats

Wang

Scabilloni

Antonini

et al. 2006

Laboratory Investigation

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Two of the common features of inflammatory lung diseases are the increased production of pulmonary surfactant and the induction of lung cell apoptosis. However, the relationship between these two events has not been addressed. To investigate the role of surfactant in pulmonary inflammation and apoptosis, we instilled natural lung surfactant (Survanta) (1.6-12.5 mg) into the rat lungs and determined the number of alveolar macrophages (AMs) and apoptotic lung cells. High-dose treatments of Survanta (46.25 mg/rat) caused an increase in macrophage cell influx and lung cell apoptosis at 4 weeks post-treatment. In vitro studies using lavaged macrophages showed Survanta did not cause apoptosis. We then examined the role of Survanta on ability of macrophages phagocytizing apoptotic cells. This study demonstrated that macrophages were able to eliminate apoptotic cells more efficiently in the absence of surfactant than in its presence. Keywords: Survanta; rat lung; apoptosis; clearance; alveolar macrophage Lung surfactant is synthesized by alveolar epithelial type II cells and is composed of approximately 80% phospholipids, 10% proteins and 10% neutral lipids. Pulmonary surfactant exists in two major compartments in the lung: the intracellular or storage compartment in the cytoplasm of alveolar type II cells and the extracellular compartment in the alveoli and distal airways. Under normal circumstances, these two pools of surfactant are maintained relatively constant. Alveolar macrophages (AMs) and type II cells are responsible for degradation of the surfactant 1,2 and exhibit increased lipid uptake and degradation in inflamed animal lungs. 3 Many toxicants, both chemical and particulate, appear to interfere with this balance. 4

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Essential roles of the Fas-Fas ligand pathway in the development of pulmonary fibrosis

Cited by 326 publications

References 32 publications

Gene expression analysis reveals matrilysin as a key regulator of pulmonary fibrosis in mice and humans

Gene expression analysis reveals matrilysin as a key regulator of pulmonary fibrosis in mice and humans

Bleomycin induces the extrinsic apoptotic pathway in pulmonary endothelial cells

Role of lung surfactant in phagocytic clearance of apoptotic cells by macrophages in rats

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