Time-Dependent Apoptosis of Alveolar Macrophages From Rats Exposed to Bleomycin: Involvement of TNF Receptor 2

Zhao, Hongwen; Hu, Shuiying; Barger, Mark; H., J. K.; Castranova, Vincent; C., J. Y.

doi:10.1080/15287390490471569

Cited by 19 publications

(16 citation statements)

References 38 publications

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“…TNFα is a multifunctional cytokine implicated in the pathogenesis of a number of pulmonary disorders including acute respiratory distress syndrome and idiopathic pneumonia, as well as tissue injury induced by endotoxin, bleomycin, silica and asbestos (Liu et al, 2001;Pryhuber et al, 2003;Shimabukuro et al, 2003;Bhatia and Moochhala, 2004;Zhao et al, 2004;Shukla et al, 2005;Ke et al, 2006;Mukhopadhyay et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Regulation of caveolin-1 expression, nitric oxide production and tissue injury by tumor necrosis factor-α following ozone inhalation

Fakhrzadeh

Laskin²,

Laskin

2008

Toxicology and Applied Pharmacology

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Alveolar macrophages (AM) and inflammatory mediators including nitric oxide and peroxynitrite contribute to ozone-induced lung injury. The generation of these mediators is regulated, in part, by the transcription factor NF-κB. We previously demonstrated a critical role for NF-κB p50 in the ozone-induced injury. In the present studies mechanisms regulating NF-κB activation in the lung after ozone inhalation were analyzed. Treatment of wild type (WT) mice with ozone (0.8 ppm, 3 h) resulted in a rapid increase in NF-κB binding activity in AM, which persisted for at least 12 h. This was not evident in mice lacking TNFα which are protected from ozone-induced injury; there was also no evidence of nitric oxide or peroxynitrite production in lungs from these animals. These data demonstrate that TNFα plays a role in NF-κB activation and toxicity. TNFα signaling involves PI-3-kinase (PI3K)/protein kinase B (PKB), and p44/42 MAP kinase (MAPK) which are important in NF-κB activation. Ozone Inhalation resulted in rapid and transient increases in p44/42 MAPK and PI3K/PKB in AM from WT mice, which was evident immediately after exposure. Caveolin-1, a transmembrane protein that negatively regulates PI3K/PKB and p44/42 MAPK signaling, was downregulated in AM from WT mice after ozone exposure. In contrast, ozone had no effect on caveolin-1, PI3K/PKB or p44/42 MAPK expression in AM from TNFα knockout mice. These data, together with our findings that TNFα suppressed caveolin-1 in cultured AM, suggest that TNFα and downstream signaling mediate activation of NF-κB and the regulation of inflammatory genes important in ozone toxicity, and that this process is linked to caveolin-1.

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Section: Discussionmentioning

confidence: 99%

Regulation of caveolin-1 expression, nitric oxide production and tissue injury by tumor necrosis factor-α following ozone inhalation

Fakhrzadeh

Laskin²,

Laskin

2008

Toxicology and Applied Pharmacology

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“…However, if alveolar macrophages are depleted using clodronate-loaded liposomes or the administration of diphtheria toxin to CD11c-diphtheria toxin receptor mice, they can be restored by monocyte-derived interstitial macrophages (7). The instillation of bleomycin induces the apoptosis of alveolar macrophages (34)(35)(36), which are then reconstituted from bone marrow-derived cells. Siglec F, which is typically considered an eosinophil marker (37), is highly expressed in murine alveolar macrophages, and when used in combination with CD11c or CD64, provides the most accurate identification of alveolar macrophages in the mouse lung.…”

Section: Discussionmentioning

confidence: 99%

Flow Cytometric Analysis of Macrophages and Dendritic Cell Subsets in the Mouse Lung

Misharin

Morales‐Nebreda

Mutlu

et al. 2013

Am J Respir Cell Mol Biol

752

712

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The lung hosts multiple populations of macrophages and dendritic cells, which play a crucial role in lung pathology. The accurate identification and enumeration of these subsets are essential for understanding their role in lung pathology. Flow cytometry is a mainstream tool for studying the immune system. However, a systematic flow cytometric approach to identify subsets of macrophages and dendritic cells (DCs) accurately and consistently in the normal mouse lung has not been described. Here we developed a panel of surface markers and an analysis strategy that accurately identify all known populations of macrophages and DCs, and their precursors in the lung during steady-state conditions and bleomycin-induced injury. Using this panel, we assessed the polarization of lung macrophages during the course of bleomycin-induced lung injury. Alveolar macrophages expressed markers of alternatively activated macrophages during both acute and fibrotic phases of bleomycin-induced lung injury, whereas markers of classically activated macrophages were expressed only during the acute phase. Taken together, these data suggest that this flow cytometric panel is very helpful in identifying macrophage and DC populations and their state of activation in normal, injured, and fibrotic lungs.Keywords: pulmonary macrophages; alveolar macrophages; interstitial macrophages; macrophage polarization; lung fibrosis Cells of the innate immune system, and especially myeloid cells such as neutrophils, eosinophils, monocytes, macrophages (alveolar and interstitial), and dendritic cells (DCs, i.e., plasmacytoid DCs, CD1031 DCs, and CD11b 1 DCs), play an important role in lung development and physiology, and contribute to important lung diseases, including pulmonary infection, cancer, asthma, chronic obstructive pulmonary disease, and pulmonary fibrosis (1-5). Alveolar and interstitial lung macrophages exhibit different origins and life spans in lungs, and have been identified as key regulators of pathological and reparative processes. Alveolar macrophages, which are considered tissue-resident macrophages, populate lung tissue during early embryogenesis and remain viable for prolonged periods, with minimal replenishment from bone marrow-derived monocytes (6). In contrast, interstitial macrophages originate from bone marrow-derived monocytes and have a shorter half-life (7,8). In recent studies, several groups of investigators suggested that these two populations of lung macrophages play opposing roles in lung injury. Alveolar macrophages appear to limit neutrophil influx into the lung during acute lung injury (9) or chronic exposure to organic dust (10), whereas interstitial macrophages promote neutrophil extravasation (11,12). An additional layer of complexity is added by the phenotypic plasticity of macrophages. Classically activated macrophages (sometimes referred to as M1-polarized) have been suggested to promote the development of acute lung injury, whereas alternatively activated macrophages (M2) may play a role in limiting or resolving lu...

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“…Bleomycin has been shown to induce alveolar macrophage apoptosis in experimental models [28,29], while intratracheal administration of apoptotic macrophages to the lungs of rats causes increased macrophage infiltration and apoptosis, and increased collagen deposition [30,31]. Increased macrophage expression of Bcl-x and Bax proteins, as well as caspases-1 and -3 in bleomycin-induced fibrosis [14,32], and Bcl-2 and Fas expression in alveolar macrophages of patients with IPF, has been reported [33,34].…”

Section: Macrophagesmentioning

confidence: 99%

Apoptosis in lung injury and fibrosis

Xifteri²,

et al. 2008

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Pulmonary fibrosis is characterised by fibroblast accumulation and alveolar epithelium denudation. Increased apoptosis of alveolar epithelial cells and decreased apoptosis of fibroblasts may play an important role in the pathogenesis of disease. Inflammatory cells can modulate apoptosis of other cell types, both by removal of apoptotic debris and by cytokine production, thus preserving a pro-fibrotic environment. In the present review, some of the mechanisms by which apoptosis may contribute to the pathogenesis of idiopathic pulmonary fibrosis are described.

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Time-Dependent Apoptosis of Alveolar Macrophages From Rats Exposed to Bleomycin: Involvement of TNF Receptor 2

Cited by 19 publications

References 38 publications

Regulation of caveolin-1 expression, nitric oxide production and tissue injury by tumor necrosis factor-α following ozone inhalation

Regulation of caveolin-1 expression, nitric oxide production and tissue injury by tumor necrosis factor-α following ozone inhalation

Flow Cytometric Analysis of Macrophages and Dendritic Cell Subsets in the Mouse Lung

Apoptosis in lung injury and fibrosis

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