Lung Transplant Airway Hypoxia

Dhillon, Gundeep; Zamora, Martin R.; Roos, Justus E.; Sheahan, Deirdre E.; Sista, Ramachandra; Starre, Pieter R. van der; Weill, David; Nicolls, Mark R.

doi:10.1164/rccm.200910-1573oc

Cited by 69 publications

(16 citation statements)

References 39 publications

(51 reference statements)

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“…Blood supply to the airways in lung transplant recipients, in contrast to the normal dual circulation, presumably comes from the deoxygenated pulmonary artery circulation 41 . Therefore, from the outset, lung transplant airways have an impaired microcirculation due to the lack of bronchial artery restoration, which, we have recently demonstrated, results in relative airway tissue hypoxia in lung transplant patients 42 . We have hypothesized that this baseline airway hypoxia may be a diathesis for chronic rejection in lung transplant recipients 42 , and therapies which preserve microvascular integrity may be especially relevant.…”

Section: Discussionmentioning

confidence: 94%

CD4 ⁺ T Cells and Complement Independently Mediate Graft Ischemia in the Rejection of Mouse Orthotopic Tracheal Transplants

Khan

Jiang

Dhillon

et al. 2011

Circulation Research

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146

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Rationale While microvascular injury is associated with chronic rejection, the cause of tissue ischemia during alloimmune injury is not yet elucidated. Objective We investigated the contribution of T lymphocytes and complement to microvascular injury-associated ischemia during acute rejection of mouse tracheal transplants. Methods and Results Using novel techniques to assess microvascular integrity and function, we evaluated how lymphocyte subsets and complement specifically affect microvascular perfusion and tissue oxygenation in MHC-mismatched transplants. To characterize T cell effects on microvessel loss and recovery, we transplanted functional airway grafts in the presence and absence of CD4+ and CD8+ T cells. To establish the contribution of complement-mediated injury to the allograft microcirculation, we transplanted C3-deficient and C3-inhibited recipients. We demonstrated that CD4+ T cells and complement are independently sufficient to cause graft ischemia. CD8+ T cells were required for airway neovascularization to occur following CD4-mediated rejection. Activation of antibody-dependent complement pathways mediated tissue ischemia even in the absence of cellular rejection. Complement inhibition by CR2-Crry attenuated graft hypoxia, complement/antibody deposition on vascular endothelium and promoted vascular perfusion by enhanced angiogenesis. Finally, there was a clear relationship between the burden of tissue hypoxia (ischemia × time duration) and the development of subsequent airway remodeling. Conclusions These studies demonstrated that CD4+ T cells and complement operate independently to cause transplant ischemia during acute rejection and that sustained ischemia is a precursor to chronic rejection.

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Section: Discussionmentioning

confidence: 94%

CD4 ⁺ T Cells and Complement Independently Mediate Graft Ischemia in the Rejection of Mouse Orthotopic Tracheal Transplants

Khan

Jiang

Dhillon

et al. 2011

Circulation Research

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146

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“…The mechanisms for chronic loss could also be due to MMPs that are known to be up regulated post lung transplantation (40-41), or perhaps mediated by chronic airway hypoxia known to occur post lung transplantation which can also enhance complement activation (42-44). Indeed, lung transplantation airway hypoxia has been implicated in fibrosis that could culminate in OB(43). While intriguing, the technical limitations of bronchial artery re-anastomosis in both mice and humans precludes our ability to directly answer this question.…”

Section: Discussionmentioning

confidence: 99%

Role of Complement Activation in Obliterative Bronchiolitis Post–Lung Transplantation

Suzuki

Lasbury

Fan

et al. 2013

The Journal of Immunology

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Obliterative bronchiolitis (OB) post lung transplantation involves IL-17 regulated autoimmunity to type V collagen and alloimmunity, which could be enhanced by complement activation. However, the specific role of complement activation in lung allograft pathology, IL-17 production, and OB are unknown. The current study examines the role of complement activation in OB. Complement regulatory protein (CRP) (CD55, CD46, Crry/CD46) expression was down regulated in human and murine OB; and C3a, a marker of complement activation, was up regulated locally. IL-17 differentially suppressed Crry expression in airway epithelial cells in vitro. Neutralizing IL-17 recovered CRP expression in murine lung allografts and decreased local C3a production. Exogenous C3a enhanced IL-17 production from alloantigen or autoantigen (type V collagen) reactive lymphocytes. Systemically neutralizing C5 abrogated the development of OB, reduced acute rejection severity, lowered systemic and local levels of C3a and C5a, recovered CRP expression, and diminished systemic IL-17 and IL-6 levels. These data indicated that OB induction is in part complement dependent due to IL-17 mediated down regulation of CRPs on airway epithelium. C3a and IL-17 are part of a feed forward loop that may enhance CRP down regulation, suggesting that complement blockade could be a therapeutic strategy for OB.

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“…Blood supply to the airways in lung transplant recipients, in contrast to the normal dual circulation, presumably comes from the deoxygenated pulmonary artery circulation (Nicolls and Zamora 2010). Therefore, from the outset, lung transplant airways have an impaired microcirculation due to the lack of bronchial artery restoration, which, we have recently demonstrated, results in relative airway tissue hypoxia in lung transplant patients (Dhillon et al 2010). We have hypothesized that this baseline airway hypoxia may be a diathesis for chronic rejection in lung transplant recipients (Dhillon et al 2010) and therapies which preserve microvascular integrity may be especially relevant.…”

Section: 9 Complement-mediated Microvascular Injury In Transplantementioning

confidence: 99%

Complement-Mediated Microvascular Injury Leads to Chronic Rejection

Khan

Nicolls

2012

Complement Therapeutics

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Microvascular loss may be an unappreciated root cause of chronic rejection for all solid organ transplants. As the only solid organ transplant that does not undergo primary systemic arterial revascularization at the time of surgery, lung transplants rely on the establishment of a microcirculation and are especially vulnerable to the effects of microvascular loss. Microangiopathy, with its attendant ischemia, can lead to tissue infarction and airway fibrosis. Maintaining healthy vasculature in lung allografts may be critical for preventing terminal airway fibrosis, also known as the bronchiolitis obliterans syndrome (BOS). BOS is the major obstacle to lung transplant success and affects up to 60% of patients surviving 5 years. The role of complement in causing acute microvascular loss and ischemia during rejection has recently been examined using the mouse orthotopic tracheal transplantation; this is an ideal model for parsing the role of airway vasculature in rejection. Prior to the development of airway fibrosis in rejecting tracheal allografts, C3 deposits on the vascular endothelium just as tissue hypoxia is first detected. With the eventual destruction of vessels, microvascular blood flow to the graft stops altogether for several days. Complement deficiency and complement inhibition lead to markedly improved tissue oxygenation in transplants, diminished airway remodeling, and accelerated vascular repair. CD4+ T cells and antibody-dependent complement activity independently mediate vascular destruction and sustained tissue ischemia during acute rejection. Consequently, interceding against complement-mediated microvascular injury with adjunctive therapy during acute rejection episodes, in addition to standard immunosuppression which targets CD4+ T cells, may help prevent the subsequent development of chronic rejection.

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Lung Transplant Airway Hypoxia

Abstract: Despite pulmonary artery blood being shunted to transplanted lungs after transplantation, grafts are hypoxic compared with both native (diseased) and control airways. Airway hypoxia may be due to the lack of radiologically demonstrable BAs after lung transplantation.

Cited by 69 publications

References 39 publications

CD4 ⁺ T Cells and Complement Independently Mediate Graft Ischemia in the Rejection of Mouse Orthotopic Tracheal Transplants

CD4 ⁺ T Cells and Complement Independently Mediate Graft Ischemia in the Rejection of Mouse Orthotopic Tracheal Transplants

Role of Complement Activation in Obliterative Bronchiolitis Post–Lung Transplantation

Complement-Mediated Microvascular Injury Leads to Chronic Rejection

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Lung Transplant Airway Hypoxia

Abstract: Despite pulmonary artery blood being shunted to transplanted lungs after transplantation, grafts are hypoxic compared with both native (diseased) and control airways. Airway hypoxia may be due to the lack of radiologically demonstrable BAs after lung transplantation.

Cited by 69 publications

References 39 publications

CD4 + T Cells and Complement Independently Mediate Graft Ischemia in the Rejection of Mouse Orthotopic Tracheal Transplants

CD4 + T Cells and Complement Independently Mediate Graft Ischemia in the Rejection of Mouse Orthotopic Tracheal Transplants

Role of Complement Activation in Obliterative Bronchiolitis Post–Lung Transplantation

Complement-Mediated Microvascular Injury Leads to Chronic Rejection

Contact Info

Product

Resources

About

CD4 ⁺ T Cells and Complement Independently Mediate Graft Ischemia in the Rejection of Mouse Orthotopic Tracheal Transplants

CD4 ⁺ T Cells and Complement Independently Mediate Graft Ischemia in the Rejection of Mouse Orthotopic Tracheal Transplants