Increased surfactant protein‐D and foamy macrophages in smoking‐induced mouse emphysema

Hirama, Noriyuki; Shibata, Yoko; Otake, Kazuhisa; Machiya, Jun-ichi; Wada, Toshihiro; Inoue, Sumito; Abe, Shuichi; Takabatake, Noriaki; Sata, Makoto; Kubota, Isao

doi:10.1111/j.1440-1843.2006.01009.x

Cited by 48 publications

(59 citation statements)

References 43 publications

(86 reference statements)

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“…The increased C/EBPb expression after exposure to SCM is in accordance with a mouse model where increased C/EBPb levels occurred in emphysema lungs following daily exposure to cigarette smoke over a period of 6 months [13]. Interestingly, C/EBPb was shown to be a negative regulator of elastin expression, a structural component of the lung alveoli [12].…”

Section: Discussionsupporting

confidence: 55%

“…Finally we studied the effect of two important inflammatory and remodelling read-outs, IL-8 and elastin, which are known to be regulated by C/EBPs [12,13,22]. As shown in figure 6, SCM significantly increased IL-8 expression (n53; p,0.05) ( fig.…”

Section: Scm-induced Il-8 and Reduced Functional Elastin Levelsmentioning

confidence: 99%

“…C/EBPs are an important family of transcription factors that regulate cell differentiation, cell cycle progression and the expression of many cytokines and chemokines relevant to COPD and emphysema [10,11]. In addition, C/EBPb was shown to inhibit the transcription of elastin [12] and was elevated in emphysema lungs [13]. In airway smooth muscle (ASM) cells of asthma patients, the expression of C/EBPa was reduced, due to an impaired translation of the mRNA, which was associated with a faster proliferation rate [14,15] and may be related to the hyperplasia of ASM cells in the lungs of asthma patients [16].…”

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confidence: 99%

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Cigarette smoke inhibits lung fibroblast proliferation by translational mechanisms

Miglino¹,

Roth²,

Lardinois³

et al. 2011

European Respiratory Journal

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Cigarette smoke is a major cause of chronic obstructive pulmonary disease (COPD) and emphysema. Although cigarette smoke represses cellular proliferation, the molecular mechanisms underlying this phenomenon are unknown. CCAAT/enhancer-binding proteins (C/EBPs) are key regulators of cell cycle progression, differentiation and pro-inflammatory gene expression, are regulated predominantly at the translational level and may be involved in the pathogenesis of COPD. The aim of this study was to assess the effect of cigarette smoke on proliferation and the expression and translational regulation of C/EBPa and C/EBPb in nondiseased primary human lung fibroblasts.Fibroblasts were exposed to cigarette smoke-conditioned medium (10% and 20% for 24 h). Proliferation was determined by [ 3 H]thymidine incorporation. Protein expression levels were determined by immunoblotting and translation was monitored using a translation control reporter system.Cigarette smoke significantly reduced fibroblast proliferation and significantly upregulated fulllength C/EBPa and C/EBPb proteins due to a shift in the translational control of CEBPA and CEBPB mRNAs. This shift involved the re-initiation of mRNA translation via the regulatory upstream open reading frame, which coincided with increased interleukin-8 release and a decrease in functional elastin level.These findings provide a novel mechanism to understanding the tissue remodelling observed in the lungs of COPD patients.

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Section: Discussionsupporting

confidence: 55%

Section: Scm-induced Il-8 and Reduced Functional Elastin Levelsmentioning

confidence: 99%

mentioning

confidence: 99%

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Cigarette smoke inhibits lung fibroblast proliferation by translational mechanisms

Miglino¹,

Roth²,

Lardinois³

et al. 2011

European Respiratory Journal

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“…These abnormalities are similar to those seen in patients and animal models with emphysema (21,39,40), but the underlying mechanism of pathogenesis has not been elucidated. Because AMs have been shown to play a pivotal role in the pathogenesis of emphysema, we determined and An extensive accumulation of the AMs occurs in the alveoli of Ig-Hepta Ϫ/Ϫ mice as early as 3 weeks of age and progressively increases thereafter (27,28).…”

Section: Discussionsupporting

confidence: 56%

Targeted Disruption of Ig-Hepta/Gpr116 Causes Emphysema-like Symptoms That Are Associated with Alveolar Macrophage Activation

Ariestanti

Ando

Hirose

et al. 2015

Journal of Biological Chemistry

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Background: Ig-Hepta knock-out mice exhibit emphysema-like symptoms, but their pathogenesis remains unclear. Results: In Ig-Hepta knock-out mice, alveolar macrophages are activated and release matrix metalloproteinases through reactive oxygen species-mediated nuclear factor-B activation. Conclusion: Ig-Hepta is likely to negatively regulate macrophage function and inflammation in the alveoli. Significance: These findings reveal a novel mechanism for maintaining lung homeostasis and immune regulation.

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“…Previously, we have reported the induction of Fra-1 by CS in bronchial epithelial cells, mainly at the transcription level (13). Elevated levels of Fra-1 expression have been reported in the lungs of mice that had developed emphysema after exposure to CS (17), but the exact role of Fra-1 in mediating CS-induced lung inflammatory responses and other changes associated with the development of COPD are not known in vivo. Given the important role played by macrophage recruitment and activation in mediating CS-induced responses in COPD, we sought to determine the role of Fra-1/ AP-1 signaling in mediating macrophagespecific lung inflammatory responses induced by CS.…”

mentioning

confidence: 99%

Myeloid-Specific Fos-Related Antigen-1 Regulates Cigarette Smoke–Induced Lung Inflammation, Not Emphysema, in Mice

Vaz

Rajasekaran

Potteti

et al. 2015

Am J Respir Cell Mol Biol

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Heightened lung inflammation is a cardinal feature of chronic obstructive pulmonary disease (COPD). Cigarette smoke (CS)-induced macrophage recruitment and activation, accompanied by abnormal secretion of a number of inflammatory cytokines and matrix metalloproteinases, play a major role in the pathophysiology of COPD. The Fos-related antigen-1 (Fra-1) transcription factor differentially regulates several cellular processes that are implicated in COPD, such as inflammation and immune responses, cell proliferation and death, and extracellular remodeling. Although CS stimulates Fra-1 expression in the lung, the precise role of this transcription factor in the regulation of CS-induced lung inflammation in vivo is poorly understood. Here, we report that myeloid-specific Fra-1 signaling is important for CS-induced lung macrophagic inflammatory response. In response to chronic CS exposure, mice with Fra-1 specifically deleted in myeloid cells showed reduced levels of CS-induced lung macrophagic inflammation, accompanied by decreased expression levels of proinflammatory cytokines compared with their wild-type counterparts. Consistent with this result, bone marrow-derived Fra-1-null macrophages treated with CS showed decreased levels of proinflammatory mediators and matrix metalloproteinases. Interestingly, deletion of Fra-1 in myeloid cells did not affect the severity of emphysema. We propose that Fra-1 plays a key role in promoting chronic CS-induced lung macrophagic inflammation in vivo, and that targeting this transcription factor may be useful in dampening persistent lung inflammation in patients with COPD.Keywords: emphysema; inflammation; activator protein-1; lung; macrophages Clinical RelevancePersistent macrophagic inflammation in the smoker's lung has been implicated in the development and perpetuation of chronic obstructive pulmonary disease (COPD). Here, we demonstrate, using a tissue-specific knockout model, that Fosrelated antigen-1 (Fra-1) transcription factor signaling in myeloid cells plays a key role in promoting chronic cigarette smoke-induced lung macrophagic inflammation in vivo. Thus, either depletion or inhibition of Fra-1 activity may be useful in dampening lung inflammation in patients with COPD.Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of chronic morbidity and mortality in the United States, and is projected to rank fifth in 2020 in burden of disease worldwide. The disease is characterized by chronic inflammation of peripheral and central airways, increased thickness of airway walls, and destruction of alveolar septa, ultimately leading to the destruction of the alveolar walls (1). Although cigarette smoking is a major risk factor for COPD, the exact mechanism(s) underlying cigarette smoke (CS)-induced lung inflammation and emphysema is not yet fully understood and Author Contributions: M.V. and S.P.R. were involved in the conception, delineation of hypotheses, and design of the study, as well as the analysis and interpretation of data; M.V. performed in v...

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Increased surfactant protein‐D and foamy macrophages in smoking‐induced mouse emphysema

Abstract: The accumulation of foamy alveolar macrophages may play a key role in the development of smoking-induced emphysema. Increased SP-D may play a protective role in the development of smoking-induced emphysema, in part by preventing alveolar cell death.

Cited by 48 publications

References 43 publications

Cigarette smoke inhibits lung fibroblast proliferation by translational mechanisms

Cigarette smoke inhibits lung fibroblast proliferation by translational mechanisms

Targeted Disruption of Ig-Hepta/Gpr116 Causes Emphysema-like Symptoms That Are Associated with Alveolar Macrophage Activation

Myeloid-Specific Fos-Related Antigen-1 Regulates Cigarette Smoke–Induced Lung Inflammation, Not Emphysema, in Mice

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