IL-13 Is Pivotal in the Fibro-Obliterative Process of Bronchiolitis Obliterans Syndrome

Keane, Michael P.; Gomperts, Brigitte N.; Weigt, S. Sam; Xue, Ying; Burdick, Marie D.; Nakamura, Hiromi; Zisman, David A.; Ardehali, A.; Saggar, Rajan; Lynch, Joseph P.; Hogaboam, Cory M.; Kunkel, Steven L.; Lukacs, Nicholas W.; Ross, David J.; Grusby, Michael J.; Strieter, Robert M.; Belperio, John A.

doi:10.4049/jimmunol.178.1.511

Cited by 78 publications

(50 citation statements)

References 39 publications

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“…Prior studies have provided considerable evidence that targeting the IL-13 pathway may be a way of controlling pulmonary inflammation and fibrosis, which are recognized as key pathological changes in a broad spectrum of respiratory diseases, including asthma (25), bronchiolitis obliterans syndrome (26), and interstitial lung diseases (27). In the current study, we detected increased levels of IL-13 in lung homogenates of mice exposed to silica particles 28 d postchallenge.…”

Section: Discussionsupporting

confidence: 57%

IL-13 Immunotoxin Accelerates Resolution of Lung Pathological Changes Triggered by Silica Particles in Mice

Ferreira

Arantes

Nascimento

et al. 2013

The Journal of Immunology

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Instillation of silica into the lungs of rodents results in pathological changes that strongly mimic human silicosis, an occupational lung disease marked by restrictive airway obstruction, inflammation, and fibrosis. Because IL-13 is a pivotal proinflammatory and fibrogenic cytokine, we examined whether a recombinant immunotoxin comprised of human IL-13 and a mutated form of Pseudomonas exotoxin (IL-13–PE) might affect pathological features of experimental silicosis. Mice received a single intranasal instillation of silica particles and were treated with intranasal IL-13–PE every other day from days 21 to 27 postsilica. The sensitivity of putative cell targets to IL-13–PE was also assessed in in vitro settings. Upregulation of IL-13, its receptor subunits IL-13Rα1 and IL-13Rα2, and shared receptor IL-4Rα were associated with development of granulomatous lung inflammation triggered by silica. IL-13–PE inhibited silica-induced granuloma and fibrotic responses noted at 24 h and 15 d after the last treatment. Upregulation of TNF-α, TGF-β, and chemokines, as well as increased collagen deposition and airway hyperreactivity to methacholine were all clearly sensitive to IL-13–PE. In addition, IL-13–PE inhibited both IL-13–induced proliferation of cultured lung fibroblasts from silicotic mice and silica-induced IL-8 generation from A549 cells. In conclusion, our findings show that therapeutic treatment with IL-13–PE can reverse important pathological features caused by inhalation of silica particles, suggesting that this recombinant immunotoxin is a promising molecular template in drug discovery for the treatment of silicosis.

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Section: Discussionsupporting

confidence: 57%

IL-13 Immunotoxin Accelerates Resolution of Lung Pathological Changes Triggered by Silica Particles in Mice

Ferreira

Arantes

Nascimento

et al. 2013

The Journal of Immunology

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“…21 Furthermore, numerous studies in cytokinedeficient mice and using neutralizing antibodies have demonstrated that the development of the CD4 + Th2 cell response, including the local production of IL-4 and IL-13, is strongly associated with liver fibrosis, 22,23 scleroderma, 24 and pulmonary fibrosis. [25][26][27] Stimulation of cultured fibroblasts with IL-4 or IL-13 triggers upregulation of the expression of the extracellular matrix proteins type I and III collagen. [28][29][30] Despite this, to the best of our knowledge, this study is the first report demonstrating that CD4 + Th2 cells play a key role in renal fibrosis and that a CRTH2 antagonist can slow the progression of renal fibrosis by suppressing the Th2 cell response.…”

Section: Discussionmentioning

confidence: 99%

PGD2-CRTH2 Pathway Promotes Tubulointerstitial Fibrosis

Ito

Yan

Nagata

et al. 2012

Journal of the American Society of Nephrology

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Urinary excretion of lipocalin-type PGD 2 synthase (L-PGDS), which converts PG H 2 to PGD 2 , increases in early diabetic nephropathy. In addition, L-PGDS expression in the tubular epithelium increases in adriamycin-induced nephropathy, suggesting that locally produced L-PGDS may promote the development of CKD. In this study, we found that L-PGDS-derived PGD 2 contributes to the progression of renal fibrosis via CRTH2-mediated activation of Th2 lymphocytes. In a mouse model, the tubular epithelium synthesized L-PGDS de novo after unilateral ureteral obstruction (UUO). L-PGDS-knockout mice and CRTH2-knockout mice both exhibited less renal fibrosis, reduced infiltration of Th2 lymphocytes into the cortex, and decreased production of the Th2 cytokines IL-4 and IL-13. Furthermore, oral administration of a CRTH2 antagonist, beginning 3 days after UUO, suppressed the progression of renal fibrosis. Ablation of IL-4 and IL-13 also ameliorated renal fibrosis in the UUO kidney. Taken together, these data suggest that blocking the activation of CRTH2 by PGD 2 might be a strategy to slow the progression of renal fibrosis in CKD.

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“…The profibrotic type 2 helper T cell cytokine IL-13 is critical in the development of luminal obliteration in animal models of BO, 4,26 and increased levels of IL-13 are present in BAL fluid of human lung transplant recipients with BOS. 26 Previously, myofibroblasts in human BO lesions expressed IL-13 receptor ␣1, the receptor chain necessary for signaling by IL-13.…”

Section: Lr-mscs Isolated From Normal Human Lung Allografts Demonstramentioning

confidence: 99%

“…26 Previously, myofibroblasts in human BO lesions expressed IL-13 receptor ␣1, the receptor chain necessary for signaling by IL-13. 4 LR-MSCs demonstrated significant expression of this receptor by both flow cytometry and immunofluorescence microscopy ( Figure 2, A nofluorescence (P Ͻ 0.0001, Figure 2C).…”

Section: Lr-mscs Isolated From Normal Human Lung Allografts Demonstramentioning

confidence: 99%

Resident Tissue-Specific Mesenchymal Progenitor Cells Contribute to Fibrogenesis in Human Lung Allografts

Walker

Badri

Wettlaufer

et al. 2011

The American Journal of Pathology

102

105

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Fibrotic obliteration of the small airways leading to progressive airflow obstruction, termed bronchiolitis obliterans syndrome (BOS), is the major cause of poor outcomes after lung transplantation. We recently demonstrated that a donor-derived population of multipotent mesenchymal stem cells (MSCs) can be isolated from the bronchoalveolar lavage (BAL) fluid of human lung transplant recipients. Herein, we study the organ specificity of these cells and investigate the role of local mesenchymal progenitors in fibrogenesis after lung transplantation. We demonstrate that human lung allograft-derived MSCs uniquely express embryonic lung mesenchyme-associated transcription factors with a 35,000-fold higher expression of forkhead/winged helix transcription factor forkhead box ( Chronic allograft rejection develops in up to 60% of patients who undergo lung transplantation by 5 years and is the leading cause of poor long-term outcomes after lung transplantation.1 As with other solid organ transplants, chronic allograft rejection in the lung manifests as a fibrotic response to repeated immune and nonimmune insults, leading to narrowing and obliteration of the small airways, a lesion termed bronchiolitis obliterans (BO). 2Subepithelial and/or intraluminal infiltration by myofibroblasts, differentiated mesenchymal cells with augmented collagen secretory and contractile functions, 3 is noted in human biopsy specimens that demonstrate BO.4 BO presents clinically as an obstructive ventilatory defect termed BO syndrome (BOS).5 BOS is the major cause of graft failure and long-term mortality, with no effective treatment options. 6,7 Understanding the origin of effector myofibroblasts in fibrotic lesions of BO is critical for therapeutic targeting of mechanisms of cell recruitment/differentiation.One potential source of mesenchymal cells participating in this disorganized repair response is the mesenchymal progenitors residing in the graft. The embryonic lung mesenchyme is derived from splanchnic mesoderm during orSupported by grants (R01DK082481 to P.H.K.; RO1HL094311 to M.P.-G.; RO1HL094622

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IL-13 Is Pivotal in the Fibro-Obliterative Process of Bronchiolitis Obliterans Syndrome

Cited by 78 publications

References 39 publications

IL-13 Immunotoxin Accelerates Resolution of Lung Pathological Changes Triggered by Silica Particles in Mice

IL-13 Immunotoxin Accelerates Resolution of Lung Pathological Changes Triggered by Silica Particles in Mice

PGD2-CRTH2 Pathway Promotes Tubulointerstitial Fibrosis

Resident Tissue-Specific Mesenchymal Progenitor Cells Contribute to Fibrogenesis in Human Lung Allografts

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