Important Roles for Macrophage Colony-stimulating Factor, CC Chemokine Ligand 2, and Mononuclear Phagocytes in the Pathogenesis of Pulmonary Fibrosis

Baran, Christopher P.; Opalek, Judy M.; McMaken, Sara; Newland, Christie A.; O’Brien, James M.; Hunter, Melissa; Bringardner, Benjamin D.; Monick, Martha M.; Brigstock, David R.; Stromberg, Paul C.; Hunninghake, Gary W.; Marsh, Clay B.

doi:10.1164/rccm.200609-1279oc

Cited by 158 publications

(172 citation statements)

References 61 publications

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“…Effects of age and gender on serum CCL2 and CXCL8 concentrations were not significant. In humans, both CXCL8 and CCL2 concentrations were found to be increased in blood (Ziegenhagen et al, 1998a;Suga et al, 1999;Fujiwara et al, 2012) and bronchoalveolar lavage fluid (BALF) (Capelli et al, 2005;Antoniou et al, 2006;Baran et al, 2007) of IPF patients compared with healthy volunteers and correlated with lung function (Capelli et al, 2005;Emad and Emad, 2007;Martina et al, 2009;Vasakova et al, 2009), disease progression (Ziegenhagen et al, 1998b;Totani et al, 2002), and outcome (Shinoda et al, 2009;Richards et al, 2012). Furthermore, several studies suggested an involvement of the chemokine CCL2 in the pathogenesis of IPF, notably through its action on resident pulmonary fibroblast and circulating fibrocytes, promoting the generation of abundant extracellular matrix in the lungs (Gharaee-Kermani et al, 1996;Phillips et al, 2004;Moore et al, 2005;Inomata et al, 2014).…”

Section: Cxcl8 and Ccl2 Concentrationsmentioning

confidence: 99%

Evaluation of chemokines CXCL8 and CCL2, serotonin, and vascular endothelial growth factor serum concentrations in healthy dogs from seven breeds with variable predisposition for canine idiopathic pulmonary fibrosis

Roels

Krafft

Antoine

et al. 2015

Research in Veterinary Science

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The West Highland white terrier (WHWT) is particularly prone to canine idiopathic pulmonary fibrosis (CIPF). We hypothesized that higher circulating concentrations of chemokines CXCL8, CCL2, serotonin (5-HT), or vascular endothelial growth factor (VEGF) could serve as predisposing factors for CIPF development in the WHWT breed. Serum samples from 103 healthy dogs of seven different breeds variably predisposed to CIPF were collected. Serum CXCL8 concentrations were higher in healthy WHWT compared with each of the other groups of healthy dogs. Serum CCL2 concentrations were higher in healthy WHWT and Maltese compared with King Charles spaniels and Malinois Belgian shepherds. No relevant inter-breed differences were observed for serum 5-HT concentrations regarding CIPF predisposition. VEGF values from 89.3% of samples tested were below the kit detection limit. In conclusion, high CXCL8 blood concentrations and possibly CCL2 concentrations might be related to the breed predisposition of the WHWT for CIPF and warrants further investigations.

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Section: Cxcl8 and Ccl2 Concentrationsmentioning

confidence: 99%

Evaluation of chemokines CXCL8 and CCL2, serotonin, and vascular endothelial growth factor serum concentrations in healthy dogs from seven breeds with variable predisposition for canine idiopathic pulmonary fibrosis

Roels

Krafft

Antoine

et al. 2015

Research in Veterinary Science

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“…Male mice, aged 6-12 weeks, underwent intraperitoneal injections as previously described (14). Briefly, mice were injected with 0.035 U bleomycin/g or PBS (vehicle control) on Days 1,4,8,11,15,18,22,and 25.…”

Section: Bleomycin Studiesmentioning

confidence: 99%

“…Furthermore, the E26 transformation-specific sequence (ets) family of transcription factors is linked to extracellular matrix remodeling (12,13), a process that is conserved in IPF. Our laboratory demonstrated that the hematopoietic growth factor macrophage colony-stimulating factor (M-CSF) is important in the development of pulmonary fibrosis (14), and M-CSF induces the activation of transcription factor ets-2 via phosphorylation at threonine-72 (15,16). A transgenic mouse containing hypomorphic ets-2 alleles, where the critical threonine-72 residue is mutated to alanine (ets-2 A72/A72), exhibits decreased expression of matrix metalloproteinase (MMP)-3 and MMP-9 in cells stimulated with M-CSF (17).…”

mentioning

confidence: 99%

Transcription Factor ets-2 Plays an Important Role in the Pathogenesis of Pulmonary Fibrosis

Baran¹,

Fischer²,

Nuovo³

et al. 2011

Am J Respir Cell Mol Biol

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Ets-2 is a ubiquitous transcription factor activated after phosphorylation at threonine-72. Previous studies highlighted the importance of phosphorylated ets-2 in lung inflammation and extracellular matrix remodeling, two pathways involved in pulmonary fibrosis. We hypothesized that phosphorylated ets-2 played an important role in pulmonary fibrosis, and we sought to determine the role of ets-2 in its pathogenesis. We challenged ets-2 (A72/A72) transgenic mice (harboring a mutated form of ets-2 at phosphorylation site threonine-72) and ets-2 (wild-type/wild-type [WT/WT]) control mice with sequential intraperitoneal injections of bleomycin, followed by quantitative measurements of lung fibrosis and inflammation and primary cell in vitro assays. Concentrations of phosphorylated ets-2 were detected via the single and dual immunohistochemical staining of murine lungs and lung sections from patients with idiopathic pulmonary fibrosis. Ets-2 (A72/A72) mice were protected from bleomycin-induced pulmonary fibrosis, compared with ets-2 (WT/ WT) mice. This protection was characterized by decreased lung pathological abnormalities and the fibrotic gene expression of Type I collagen, Type III collagen, a-smooth muscle actin, and connective tissue growth factor. Immunohistochemical staining of lung sections from bleomycin-treated ets-2 (WT/WT) mice and from patients with idiopathic pulmonary fibrosis demonstrated increased staining of phosphorylated ets-2 that colocalized with Type I collagen expression and to fibroblastic foci. Lastly, primary lung fibroblasts from ets-2 (A72/A72) mice exhibited decreased expression of Type I collagen in response to stimulation with TGF-b, compared with fibroblasts from ets-2 (WT/WT) mice. These data indicate the importance of phosphorylated ets-2 in the pathogenesis of pulmonary fibrosis through the expression of Type I collagen and (myo)fibroblast activation.Keywords: ets-2; Type I collagen; pulmonary fibrosis; bleomycin; fibroblast Interstitial lung diseases are a broad set of diseases that perturb lung function by affecting the space between endothelial cells of the vascular bed and alveolar epithelial cells. In normal conditions, this interstitial space consists of a minimal amount of matrix, allowing the efficient transport of oxygen and carbon dioxide. The interruption of this normal lung architecture can alter lung function. One set of lung diseases characterized by interstitial matrix deposition, the destruction of alveolar-capillary units, and functional impairment is termed idiopathic interstitial pneumonias (IIPs).The most prevalent form of IIP is idiopathic pulmonary fibrosis (IPF). Despite exhaustive research into underlying mechanisms, patients with IPF have a median survival of 3-5 years after diagnosis (1). From 1992-2003, the mortality rates for patients with IPF significantly increased, despite ongoing investigation into the molecular mechanisms of the disease (2). The only consistent treatment option is lung transplantation, although more than 30% of patients die on the w...

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“…The disadvantage of this model is that the fibrosis is patchy (depending on lung deposition of the instillate) and self-resolving beyond a certain period. While the development of fibrosis in response to bleomycin is T-cell independent (Helene et al, 1999;Szapiel et al, 1979), the development of fibrotic lesions is dependent on the release of chemokines (CCL2 or CCL12) and the recruitment of inflammatory cells including neutrophils, monocytes, and lymphocytes (Baran et al, 2007;Inoshima et al, 2004;Moore et al, 2001;Moore et al, 2006;Smith et al, 1995;Zhang et al, 1994). Pro-fibrotic cytokines (e.g.…”

Section: Bleomycinmentioning

confidence: 99%

Inflammation and Pulmonary Fibrosis

Crooks¹,

Aslam²,

Hart³

2012

Inflammatory Diseases - Immunopathology, Clinical and Pharmacological Bases

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Important Roles for Macrophage Colony-stimulating Factor, CC Chemokine Ligand 2, and Mononuclear Phagocytes in the Pathogenesis of Pulmonary Fibrosis

Cited by 158 publications

References 61 publications

Evaluation of chemokines CXCL8 and CCL2, serotonin, and vascular endothelial growth factor serum concentrations in healthy dogs from seven breeds with variable predisposition for canine idiopathic pulmonary fibrosis

Evaluation of chemokines CXCL8 and CCL2, serotonin, and vascular endothelial growth factor serum concentrations in healthy dogs from seven breeds with variable predisposition for canine idiopathic pulmonary fibrosis

Transcription Factor ets-2 Plays an Important Role in the Pathogenesis of Pulmonary Fibrosis

Inflammation and Pulmonary Fibrosis

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