TGF-beta driven lung fibrosis is macrophage dependent and blocked by Serum amyloid P

Murray, Lynne A.; Chen, Qingsheng; Kramer, Michael S.; Hesson, David P.; Argentieri, Rochelle L.; Peng, Xueyan; Gulati, Mridu; Homer, Robert J.; Russell, Thomas; Rooijen, Nico van; Elias, Jack A.; Hogaboam, Cory M.; Herzog, Erica L.

doi:10.1016/j.biocel.2010.10.013

Cited by 333 publications

(290 citation statements)

References 33 publications

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“…This relative increase in M1 over M2 macrophages during the first week of healing could have had a negative effect on bone repair at 6 weeks postoperative. The increase in Arg-1 immunoreactivity in LPS-treated mice at 14 days postoperative localized almost exclusively to the fibrous tissue in the window defect, which was much more abundant in these animals compared with the control animals and most likely reflected the profibrotic effect of the M2a macrophage subset [3,[34][35][36]. Similar macrophage-induced increases in fibrous tissue formation leading to defective healing of skin wounds have been associated with LPS-induced systemic inflammation [37].…”

Section: Discussionmentioning

confidence: 82%

Defective Bone Repair in C57Bl6 Mice With Acute Systemic Inflammation

Behrends

Hui

Gao

et al. 2017

Clinical Orthopaedics &Amp; Related Research

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Background Bone repair is initiated with a local inflammatory response to injury. The presence of systemic inflammation impairs bone healing and often leads to malunion, although the underlying mechanisms remain poorly defined. Our research objective was to use a mouse model of cortical bone repair to determine the effect of systemic inflammation on cells in the bone healing microenvironment. Question/Purposes (1) Does systemic inflammation, induced by lipopolysaccharide (LPS) administration affect the quantity and quality of regenerating bone in primary bone healing? (2) Does systemic inflammation alter vascularization and the number or activity of inflammatory cells, osteoblasts, and osteoclasts in the bone healing microenvironment? Methods Cortical defects were drilled in the femoral diaphysis of female and male C57BL/6 mice aged 5 to 9 months that were treated with daily systemic injections of LPS or physiologic saline as control for 7 days. Mice were euthanized at 1 week (Control, n = 7; LPS, n = 8), 2 weeks (Control, n = 7; LPS, n = 8), and 6 weeks (Control, n = 9; LPS, n = 8) after surgery. The quantity (bone volume per tissue volume [BV/TV]) and microarchitecture (trabecular separation and thickness, porosity) of bone in the defect were quantified with time using microCT. The presence or activity of vascular endothelial cells (CD34), macrophages (F4/80), osteoblasts (alkaline phosphatase [ALP]), and osteoclasts (tartrate-resistant acid phosphatase [TRAP]) were evaluated using histochemical analyses.The institution of one or more of the authors (JEH, PAM) has received, during the study period, funding from the Fonds de recherche Santé Québec. The remaining authors certify that neither he or she, nor a member of his or her immediate family, has funding or commercial associations (consultancies, stock ownership, equity interest, patent/licensing arrangements, etc) that might pose a conflict of interest in connection with the submitted article. Results Only one of eight defects was bridged completely 6 weeks after surgery in LPS-injected mouse bones compared with seven of nine defects in the control mouse bones (odds ratio [OR], 0.04; 95% CI, 0.003-0.560; p = 0.007). The decrease in cortical bone in LPS-treated mice was reflected in reduced BV/TV (21% ± 4% vs 39% ± 10%; p\0.01), increased trabecular separation (240 ± 36 lm vs 171 ± 29 lm; p \ 0.01), decreased trabecular thickness (81 ± 18 lm vs 110 ± 22 lm; p = 0.02), and porosity (79% ± 4% vs 60% ± 10%; p \ 0.01) at 6 weeks postoperative. Defective healing was accompanied by decreased CD34 (1.1 ± 0.6 vs 3.4 ± 0.9; p\0.01), ALP (1.9 ± 0.9 vs 6.1 ± 3.2; p = 0.03), and TRAP (3.3 ± 4.7 vs 7.2 ± 4.0; p = 0.01) activity, and increased F4/80 (13 ± 2.6 vs 6.8 ± 1.7; p \ 0.01) activity at 2 weeks postoperative. Conclusion The results indicate that LPS-induced systemic inflammation reduced the amount and impaired the quality of bone regenerated in mouse femurs. The effects were associated with impaired revascularization, decreased bone turnover by osteoblasts...

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Section: Discussionmentioning

confidence: 82%

Defective Bone Repair in C57Bl6 Mice With Acute Systemic Inflammation

Behrends

Hui

Gao

et al. 2017

Clinical Orthopaedics &Amp; Related Research

View full text Add to dashboard Cite

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“…It is noteworthy that TGF-β1, FGF10, and PDGF were dominantly over-expressed in disease, suggesting they might be disease-drivers of INSIP and IPF. Several studies uncovered TGF-β1 as a well-known pro-fibrogenic factor (7,(14)(15)(16)(17), and pirfenidone or nintedanib could be used in IPF-involved dysfunction of TGF-β1 (18)(19)(20)(21). But little is known about FGF10 and PDGF in the pathogenesis of pulmonary fibrosis and their therapeutic potential in INSIP and IPF, especially as studies have lacked human clinical relevance evidence that may identify the role of these cytokines in IIPs.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have suggested that many cytokines, including interleukins (ILs), transforming growth factor-beta (TGF-β), alpha-smooth muscle actin (α-SMA), and BMP-7 have pro-fibrogenic effects (6)(7)(8)(9). Since patients with IPF frequently exhibit fibrotic lesion and have poor prognosis, many studies have focused on the role of these cytokines in IPF, and few investigations uncover the aberrantly expressed cytokines involved in the pathogenesis of patients with INSIP.…”

Section: Introductionmentioning

confidence: 99%

Lower expression of platelet derived growth factor is associated with better overall survival rate of patients with idiopathic nonspecific interstitial pneumonia

et al. 2017

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Background: Idiopathic nonspecific interstitial pneumonia (INSIP) presents with varying degrees of interstitial inflammation and fibrosis exhibiting a uniform appearance. Lack of knowledge on the underlying mechanisms of INSIP has contributed to few effective treatment strategies. Our study is designed to explore aberrantly expressed cytokines involvement in INSIP development.Methods: Oligo GEArray was employed to detect the expression of cytokines in INSIP patients, and idiopathic pulmonary fibrosis (IPF) was setup as isotype control. Real-time PCR and immunohistochemistry analysis were used to further confirm the expression of abnormally expressed cytokines. The correlationship between cytokines expression and overall survival rate of patients with IPF and INSIP were analyzed.Results: From microarray detection, transforming growth factor-beta-1 (TGF-β1), fibroblast growth factor 10 (FGF10), and platelet derived growth factor (PDGF) were predominantly up-regulated in patients with INSIP. Real-time PCR and immunohistochemistry also showed these cytokines was abnormally expressed in INSIP. In addition to, the clinical relevance analysis demonstrated relatively lower expression of PDGF patients had longer overall survival rate than those with higher expression of PDGF.Conclusions: Our study suggests that TGF-β1, FGF10, and PDGF are required for the pathogenesis of INSIP, and may therefore be ideal targets in INSIP treatment. Moreover, INSIP patients with lower expression of PDGF had better survival rate.Keywords: Idiopathic nonspecific interstitial pneumonia (INSIP); idiopathic pulmonary fibrosis (IPF); transforming growth factor-beta-1 (TGF-β1); fibroblast growth factor 10 (FGF10); platelet derived growth factor (PDGF)

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“…Lee et al 9 created an inducible lung-specific IL-13 transgenic mouse line that exhibited a variety of abnormalities resembling human allergic airway disease but also developed progressive fibrosis in the airway and lung parenchyma. The profibrotic effect of IL-13 appears to involve, not unexpectedly, TGF-, potentially produced by profibrotic macrophages (of the " M2 " phenotype 54,55 ), but these mechanisms are not well characterized (reviewed by Wynn 8 ). After injury, lung epithelium undergoes repair and / or regeneration to repopulate the lost epithelium and resurface the area resulting in transient " fibrosis, " which resolves with time.…”

Section: Preclinical Modelsmentioning

confidence: 99%