Cyclosporine Does Not Prevent Microvascular Loss in Transplantation but Can Synergize With a Neutrophil Elastase Inhibitor, Elafin, to Maintain Graft Perfusion During Acute Rejection

Jiang, Xinguo; Nguyễn, Andy; Tian, Wen; Sung, Yon K.; Yuan, Ke; Qian, Jin; Rajadas, Jayakumar; Sallenave, Jean–Michel; Nickel, Nils; Perez, Vinicio de Jesus; Rabinovitch, Marlene; Nicolls, Mark R.

doi:10.1111/ajt.13189

Cited by 14 publications

(15 citation statements)

References 47 publications

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“…Increased levels of C3a and C5a in the BALF were reported in transfusion-related acute lung injury [23] and chronic rejection post-lung transplant [24]. Elevated tissue deposition of C5b9 was reported during acute rejection phase post-lung transplant [25]. Our studies show that active C3a and C5a levels were higher in the BALF of mice exposed to adenoviral vectors overexpressing TGF-β.…”

Section: Resultssupporting

confidence: 60%

Potential Mechanisms Underlying TGF-β-mediated Complement Activation in Lung Fibrosis

Fisher¹,

Cipolla²,

Varre³

et al. 2017

Cell Mol Med

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While our previous studies suggest that limiting bleomycin-induced complement activation suppresses TGF-β signaling, the specific hierarchical interactions between TGF-β and complement in lung fibrosis are unclear. Herein, we investigated the mechanisms underlying TGF-β-induced complement activation in the pathogenesis of lung fibrosis. C57-BL6 mice were given intratracheal instillations of adenoviral vectors overexpressing TGF-β (Ad-TGFβ) or the firefly gene-luciferase (Ad-Luc; control). Two weeks later, mice with fibrotic lungs were instilled RNAi specific to receptors for C3a or C5a-C3ar or C5ar, and sacrificed at day 28. Histopathological analyses revealed that genetic silencing of C3ar or C5ar arrested the progression of TGF-β-induced lung fibrosis, collagen deposition and content (hydroxyproline, col1a1/2); and significantly suppressed local complement activation. With genetic silencing of either C3ar or C5ar, in Ad-TGFβ-injured lungs: we detected the recovery of Smad7 (TGF-β inhibitor) and diminished local release of DAF (membrane-bound complement inhibitor); in vitro: TGF-β-mediated loss of DAF was prevented. Conversely, blockade of the TGF-β receptor prevented C3a-mediated loss of DAF in both normal primary human alveolar and small airway epithelial cells. Of the 52 miRNAs analyzed as part of the Affymetrix array, normal primary human SAECs exposed to C3a, C5a or TGF-β caused discrete and overlapping miRNA regulation related to epithelial proliferation or apoptosis (miR-891A, miR-4442, miR-548, miR-4633), cellular contractility (miR-1197) and lung fibrosis . Our studies present potential mechanisms by which TGF-β activates complement and promotes lung fibrosis.

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Section: Resultssupporting

confidence: 60%

Potential Mechanisms Underlying TGF-β-mediated Complement Activation in Lung Fibrosis

Fisher¹,

Cipolla²,

Varre³

et al. 2017

Cell Mol Med

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“…One possibility for this may be because of the potential nonspecific nature of C3aRA (68). Whereas complement deposition in the tissue was reported in lupus nephritis (69) and in acute rejection phase post-lung transplantation (53), to our knowledge, this is the first study to demonstrate elevated local soluble C5b-9-the terminal complement complex (TCC)-in a murine lung fibrosis model, and that blockade of C3aR and C5aR has protective effects. To our knowledge, this is also the first report to demonstrate the presence of significant levels of TCC in the lungs of patients with IPF.…”

Section: Discussionmentioning

confidence: 89%

“…3 B ) were suppressed by the blockade of C3aR or C5aR. Elevated tissue deposition of C5b‐9 was reported during the acute rejection phase post‐lung transplantation (53). Bleomycin‐induced soluble C5b‐9 was suppressed with the blockade of both receptors.…”

Section: Resultsmentioning

confidence: 99%

Contribution of the anaphylatoxin receptors, C3aR and C5aR, to the pathogenesis of pulmonary fibrosis

Fisher

Mickler

et al. 2016

FASEB j.

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Complement activation, an integral arm of innate immunity, may be the critical link to the pathogenesis of idiopathic pulmonary fibrosis (IPF). Whereas we have previously reported elevated anaphylatoxins—complement component 3a (C3a) and complement component 5a (C5a)—in IPF, which interact with TGF‐β and augment epithelial injury in vitro, their role in IPF pathogenesis remains unclear. The objective of the current study is to determine the mechanistic role of the binding of C3a/C5a to their respective receptors (C3aR and C5aR) in the progression of lung fibrosis. In normal primary human fetal lung fibroblasts, C3a and C5a induces mesenchymal activation, matrix synthesis, and the expression of their respective receptors. We investigated the role of C3aR and C5aR in lung fibrosis by using bleomycin‐injured mice with fibrotic lungs, elevated local C3a and C5a, and overexpression of their receptors via pharmacologic and RNA interference interventions. Histopathologic examination revealed an arrest in disease progression and attenuated lung collagen deposition (Masson's trichrome, hydroxyproline, collagen type I α 1 chain, and collagen type I α 2 chain). Pharmacologic or RNA interference‐specific interventions suppressed complement activation (C3a and C5a) and soluble terminal complement complex formation (C5b‐9) locally and active TGF‐β1 systemically. C3aR/C5aR antagonists suppressed local mRNA expressions of tgfb2, tgfbr1/2, ltbp1/2, serpine1, tsp1, bmp1/4, pdgfbb, igf1, but restored the proteoglycan, dcn. Clinically, compared with pathologically normal human subjects, patients with IPF presented local induction of C5aR, local and systemic induction of soluble C5b‐9, and amplified expression of C3aR/C5aR in lesions. The blockade of C3aR and C5aR arrested the progression of fibrosis by attenuating local complement activation and TGF‐β/bone morphologic protein signaling as well as restoring decorin, which suggests a promising therapeutic strategy for patients with IPF.—Gu, H., Fisher, A. J., Mickler, E. A., Duerson, F., III, Cummings, O. W., Peters‐Golden, M., Twigg, H. L., III, Woodruff, T. M., Wilkes, D. S., Vittal, R. Contribution of the anaphylatoxin receptors, C3aR and C5aR, to the pathogenesis of pulmonary fibrosis. FASEB J. 30, 2336–2350 (2016). http://www.fasebj.org

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“…We next investigated the local effects of il17a deficiency on the C9 components active C3a and active C5a and the terminal C9 complex soluble C5b-9. Increased levels of C3a and C5a in BALF were reported in transfusion-related acute lung injury (37) and in chronic rejection after lung transplantation (38). We have reported that BLEO injury induces local C3a and C5a levels at d 14 that persist at d 28 (26).…”

Section: Il-17a Deficiency Protects Against Bleo-induced Local C9 Actmentioning

confidence: 91%

IL‐17A deficiency mitigates bleomycin‐induced complement activation during lung fibrosis

Cipolla

Fisher

et al. 2017

The FASEB Journal

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Interleukin 17A (IL-17A) and complement (C') activation have each been implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF). We have reported that IL-17A induces epithelial injury TGF-β in murine bronchiolitis obliterans; that TGF-β and the C' cascade present signaling interactions in mediating epithelial injury; and that the blockade of C' receptors mitigates lung fibrosis. In the present study, we investigated the role of IL-17A in regulating C' in lung fibrosis. Microarray analyses of mRNA isolated from primary normal human small airway epithelial cells indicated that IL-17A (100 ng/ml; 24 h; = 5 donor lungs) induces C' components (C' factor B, , and GPCR kinase isoform 5), cytokines (, , and), and cytokine ligands (, ,, ,, and ). IL-17A induces protein and mRNA regulation of C' components and the synthesis of active C' 3a (C3a) in normal primary human alveolar type II epithelial cells (AECs). Wild-type mice subjected to IL-17A neutralization and IL-17A knockout ( ) mice were protected against bleomycin (BLEO)-induced fibrosis and collagen deposition. Further, BLEO-injured mice had diminished levels of circulating Krebs Von Den Lungen 6 (alveolar epithelial injury marker), local caspase-3/7, and local endoplasmic reticular stress-related genes. BLEO-induced local C' activation [C3a, C5a, and terminal C' complex (C5b-9)] was attenuated in mice, and IL-17A neutralization prevented the loss of epithelial C' inhibitors (C' receptor-1 related isoform Y and decay accelerating factor), and an increase in local TUNEL levels. RNAi-mediated gene silencing of in fibrotic mice arrested the progression of lung fibrosis, attenuated cellular apoptosis (caspase-3/7) and lung deposition of collagen and C' (C5b-9). Compared to normals, plasma from IPF patients showed significantly higher hemolytic activity. Our findings demonstrate that limiting complement activation by neutralizing IL-17A is a potential mechanism in ameliorating lung fibrosis.-Cipolla, E., Fisher, A. J., Gu, H., Mickler, E. A., Agarwal, M., Wilke, C. A., Kim, K. K., Moore, B. B., Vittal, R. IL-17A deficiency mitigates bleomycin-induced complement activation during lung fibrosis.

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Cyclosporine Does Not Prevent Microvascular Loss in Transplantation but Can Synergize With a Neutrophil Elastase Inhibitor, Elafin, to Maintain Graft Perfusion During Acute Rejection

Cited by 14 publications

References 47 publications

Potential Mechanisms Underlying TGF-β-mediated Complement Activation in Lung Fibrosis

Potential Mechanisms Underlying TGF-β-mediated Complement Activation in Lung Fibrosis

Contribution of the anaphylatoxin receptors, C3aR and C5aR, to the pathogenesis of pulmonary fibrosis

IL‐17A deficiency mitigates bleomycin‐induced complement activation during lung fibrosis

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