Soluble Transforming Growth Factor- β  Type III Receptor  Gene Transfection Inhibits Fibrous Airway Obliteration  in a Rat Model of Bronchiolitis Obliterans

Liu, Mingyao; Suga, Michiharu; MacLean, Alexandra A.; George, Judith A. St.; Souza, David W.; Keshavjee, Shaf

doi:10.1164/ajrccm.165.3.2102108

Cited by 47 publications

(26 citation statements)

References 30 publications

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“…MMP inhibition also did not improve epithelial repair and regeneration, suggesting that the epithelial lesion is likely primarily mediated by the alloimmune process. Interestingly, we found that administration of the MMP inhibitor during the developing phase of fibrosis (days [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28], showed even better effects to reduce the airway obliteration. This result needs to be further confirmed and the underlying mechanism is unknown.…”

Section: Discussionmentioning

confidence: 99%

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Allograft Airway Fibrosis in the Pulmonary Milieu: A Disorder of Tissue Remodeling

Sato

Liu

Anraku

et al. 2008

American Journal of Transplantation

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Obliterative bronchiolitis (OB) is thought to be a form of chronic allograft rejection. However, immunosuppressive therapy is not effective once fibrosis has developed. We hypothesize that disordered tissue remodeling is a mechanism for the pathogenesis of OB. We examined allograft airway fibrosis in an intrapulmonary tracheal transplant model of OB. Allograft airways were completely obliterated at day 21 by fibrotic tissue; however, tissue remodeling continued thereafter, as demonstrated by the change of collagen deposition density, shift from type I to type III collagen, shift from fibroblasts to myofibroblasts and shift of expression profiles and activities of matrix metalloproteinases (MMPs). We then used a broad-spectrum MMP inhibitor, SC080, to attempt to manipulate tissue remodeling. Administration of the MMP inhibitor from day 0 to day 28 reduced airway obliteration, without inhibiting T-cell activation. MMP inhibition from day 14 to day 28 showed similar effects on airway obliteration. MMP inhibition from day 21 to day 35 did not reverse the airway obliteration, but significantly reduced the collagen deposition, type III collagen and myofibroblasts in the lumen. We conclude that tissue remodeling plays a critical role in the development and maintenance of fibrosis after transplantation.

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Section: Discussionmentioning

confidence: 99%

“…PSR staining was also observed under polarized light to depict thick type I collagen and thin type III collagen as yellow-orange fibers and green-white fibers, respectively (12). Quantification of total collagen (13) and computerized morphometry for occlusive fibrosis (14) were performed as previously described.…”

Section: Histologymentioning

confidence: 99%

Allograft Airway Fibrosis in the Pulmonary Milieu: A Disorder of Tissue Remodeling

Sato

Liu

Anraku

et al. 2008

American Journal of Transplantation

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“…11,[35][36][37] Recent work using IL-13-overexpressing mice suggests that IL-13 might exert its profibrotic effects via increasing both the transcription and the activation of TGF-␤1. 38 We studied the level of TGF-␤ expression in the heterotopic tracheal allografts placed into BALB/c (IL-13 ϩ/ϩ ) recipients or IL-13 Ϫ/Ϫ recipients.…”

Section: Effect Of Il-13 In the Production Of Tgf-␤1 In Heterotopic Tmentioning

confidence: 99%

Obligatory Role for Interleukin-13 in Obstructive Lesion Development in Airway Allografts

Lama

Harada

Badri

et al. 2006

The American Journal of Pathology

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The pathogenesis of bronchiolitis obliterans (BO), a common and devastating obliterative disorder of small airways following lung transplantation, remains poorly understood. Lesions are characterized in their early stages by lymphocyte influx that evolves into dense fibrotic infiltrates. Airway specimens taken from patients with histological BO revealed infiltrating myofibroblasts, which strongly expressed the signaling chain of the high affinity interleukin-13 (IL-13) receptor IL-13R␣1. Because IL-13 has proinflammatory and profibrotic actions, a contributory role for IL-13 in BO development was examined using murine models of orthotopic and heterotopic tracheal transplantation. Compared with airway isografts, allografts exhibited a significant increase in relative IL-13 mRNA and protein levels. Allogeneic tracheas transplanted into IL-13-deficient mice were protected from BO in both transplant models. Flow cytometric analysis of orthotopic transplant tissue digests revealed markedly fewer infiltrating mononuclear phagocytes and CD3؉ T lymphocytes in IL-13-deficient recipients. Furthermore, protection from luminal obliteration, collagen deposition, and myofibroblast infiltration was observed in heterotopic airways transplanted into the IL-13 ؊/؊ recipients. Transforming growth factor-␤1 expression was significantly decreased in tracheal allografts into IL-13 ؊/؊ recipients, compared to wild-type counterparts. These human and murine data implicate IL-13 as a critical effector cytokine driving cellular recruitment and subsequent fibrosis in clinical and ex- Bronchiolitis obliterans syndrome (BOS) is the major factor limiting quality of life as well as long-term survival after lung transplantation. BO is a histological diagnosis, characterized by fibrosis and obliteration of the small airways.1 BOS, the clinical correlate of BO, is diagnosed by irreversible deterioration of pulmonary function in the absence of other causes.2 BOS is seen in up to 60% of lung transplant recipients by 5 years after transplantation. There are currently no meaningful therapeutic interventions, providing a compelling rationale to understand fully BOS pathogenesis as this may lead to development of new therapeutic approaches.Data from human as well as animal studies suggest associations between inflammatory cells/mediators and BOS. Lymphocytic bronchitis is considered a risk factor for development of BOS in humans, 3 and lymphocytic infiltration precedes development of luminal obliteration in animal models of tracheal transplantation. 4,5 Similarly, several markers of inflammation (eg, neutrophilia,(6)(7)(8)7 and monocyte chemoattractant protein-1 (MCP-1/ CCL2) 8,9 ) are predictive of development of BO in humans. However, the failure of immunosuppressive therapy and anti-inflammatory agents to demonstrate efficacy in preventing or treating this disease has focused attention on BOS as a fibroproliferative response to airway epithelial injury. Evidence for this is provided by studies suggesting a role for transforming growth factor-␤ (TGF-...

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“…11,12 As a proof of concept, studies in an animal model of OB that interrupt TGF-␤ binding to its receptor have shown reduced intraluminal airway matrix deposition. 13 The difficulty in fully understanding the biology of TGF-␤ in organ transplantation lies in reconciling these seeming dichotomous actions: its protective early up-regulation in acute rejection versus its prolonged overexpression in chronic rejection. We are investigating the latter aspects of TGF-␤1 and its downstream effectors in their involvement in the development of OB after lung transplantation.…”

mentioning

confidence: 99%

Smad3 Deficiency Ameliorates Experimental Obliterative Bronchiolitis in a Heterotopic Tracheal Transplantation Model

Ramirez

Takagawa

Sekosan

et al. 2004

The American Journal of Pathology

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Chronic allograft rejection manifested as obliterative bronchiolitis (OB) remains the single greatest impediment to long-term survival after lung transplantation. Transforming growth factor-␤1 (TGF-␤1) has been implicated in the tissue remodeling response associated with OB. Therefore, its intracellular signal transducer, Smad3, is a prime target of investigation. Herein, we examine the role of TGF-␤1, through Smad3, in the development of OB using heterotopic tracheal transplantation in wild-type and Smad3-null mice. TGF-␤1 was detectable within infiltrating mononuclear cells early after transplantation. Throughout the last 20 years, lung transplantation has evolved into an accepted treatment option for patients with end-stage lung disease because of emphysema, pulmonary fibrosis, pulmonary hypertension, and cystic fibrosis. 1 However, chronic allograft rejection manifested as obliterative bronchiolitis (OB) remains the major obstacle to long-term survival after lung transplantation. 2 Clinically, OB is characterized by airflow limitation, defined by a 20% decline in forced expiratory volume in 1 second (FEV 1 ), and is often complicated by recurrent lower respiratory tract infections. The histological hallmark of OB is the presence of obstructing intraluminal polyps comprised of fibromyxoid granulation tissue and plaques of dense submucosal eosinophilic scar on lung biopsy. OB can complicate up to 60% of lung allografts and becomes increasingly prevalent the further removed from the transplant operation. 3 Progressive OB ultimately results in worsening hypoxemia and death.Many studies on the pathogenesis of OB have concentrated on the role of cellular allogenic immune responses during OB development. However, fibroproliferation and tissue remodeling clearly play an important role in its pathogenesis because OB is characterized by the accumulation of fibroblasts and the excessive deposition of connective tissue matrix within the lumen of the affected bronchioles. The factors that initiate and maintain fibroproliferation and tissue remodeling within the airway lumen in OB have not been fully elucidated. One candidate factor is transforming growth factor (TGF)-␤, a pleiotropic cytokine with potent profibrotic activities. 4 Extensively studied in solid organ transplantation, TGF-␤ has been found to have beneficial effects on alloimmunity. For instance, overexpression of a TGF-␤ transgene leads to marked reductions in acute rejection and prolongation of graft survival in experimental heart and

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Soluble Transforming Growth Factor- β Type III Receptor Gene Transfection Inhibits Fibrous Airway Obliteration in a Rat Model of Bronchiolitis Obliterans

Cited by 47 publications

References 30 publications

Allograft Airway Fibrosis in the Pulmonary Milieu: A Disorder of Tissue Remodeling

Allograft Airway Fibrosis in the Pulmonary Milieu: A Disorder of Tissue Remodeling

Obligatory Role for Interleukin-13 in Obstructive Lesion Development in Airway Allografts

Smad3 Deficiency Ameliorates Experimental Obliterative Bronchiolitis in a Heterotopic Tracheal Transplantation Model

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