Nonclassical resident macrophages are important determinants in the development of myocardial fibrosis.

Macrophages are increasingly recognized as a potential therapeutic target in myocardial fibrosis via interactions with fibroblasts. We have characterized macrophage depletion and inhibition of nonclassical macrophage migration, in addition to direct interactions between nonclassical macrophages and fibroblasts in angiotensin II (AngII)-mediated, hypertensive myocardial fibrosis. Macrophage depletion was achieved by daily i.

Disruption of collagen homeostasis can reverse established age-related myocardial fibrosis.

Heart failure, the leading cause of hospitalization of elderly patients, is correlated with myocardial fibrosis (ie, deposition of excess extracellular matrix proteins such as collagen). A key regulator of collagen homeostasis is lysyl oxidase (LOX), an enzyme responsible for cross-linking collagen fibers. Our objective was to ameliorate age-related myocardial fibrosis by disrupting collagen cross-linking through inhibition of LOX.

The composition of ectopic lymphoid structures suggests involvement of a local immune response in cardiac allograft vasculopathy.

Background: Cardiac allograft vasculopathy (CAV) is a multifactorial pathology limiting the survival of cardiac transplants. The etiology of CAV is unclear, but antibody-mediated and cellular-mediated responses have been implicated. We, and others, have observed ectopic lymphoid structures (ELS) surrounding epicardial coronary arteries with CAV.

Impact of donor benign intimal thickening on cardiac allograft vasculopathy.

Background: Epicardial cardiac allograft vasculopathy (CAV) is commonly described as a homogeneous smooth muscle cell (SMC)-rich inward intimal lesion with the SMC oriented circumferentially around the vessel. Recent findings have called this description into question. In this study we aimed to clarify the clinical presentation of epicardial CAV.

Regulation and role of connective tissue growth factor in AngII-induced myocardial fibrosis.

Exposure of rodents to angiotensin II (AngII) is a common model of fibrosis. We have previously shown that cellular infiltration of bone marrow-derived progenitor cells (fibrocytes) occurs before deposition of extracellular matrix and is associated with the production of connective tissue growth factor (CTGF). In the present study, we characterized the role of CTGF in promoting fibrocyte accumulation and regulation after AngII exposure.

Treatment with activated protein C (aPC) is protective during the development of myocardial fibrosis: an angiotensin II infusion model in mice.

Aims: Myocardial fibrosis contributes to the development of heart failure. Activated Protein C (aPC) is a circulating anticoagulant with anti-inflammatory and cytoprotective properties. Using a model of myocardial fibrosis second to Angiotensin II (AngII) infusion, we investigated the novel therapeutic function aPC in the development of fibrosis.

Cyclosporine immunosuppression does not prevent the production of donor-specific antibody capable of mediating allograft vasculopathy.

Background: Late cardiac graft rejection, primarily mediated by allograft vasculopathy (AV), remains a major limitation to cardiac transplantation, even in the face of significant calcineurin inhibitor (CNI) immunosuppression. The role played by alloantibody in AV is unclear. Evidence that CNI immunosuppression suppresses CD4(+) T-cell function would suggest that antibody production and effector function would be severely limited in CNI-treated patients.

Fibroblast progenitor cells are recruited into the myocardium prior to the development of myocardial fibrosis.

Using an established model of myocardial hypertrophy and fibrosis after angiotensin II (AngII) infusion, our aim was to characterize the early cellular element involved in the development of myocardial fibrosis in detail. Male Lewis rats were infused with saline or AngII (0.7 mg/kg per day) for up to seven days.

Early innate immune events induced by prolonged cold ischemia exacerbate allograft vasculopathy.

Background: Ischemia/reperfusion induced innate immune injury is inescapable in solid organ transplantation. Prolonged cold ischemia exacerbates the primary manifestation of late graft rejection, allograft vasculopathy (AV). The relationship between prolonged cold ischemia and late graft events is unclear and the subject of this study.

Myocardial fibrosis in response to Angiotensin II is preceded by the recruitment of mesenchymal progenitor cells.

Myocardial fibrosis is characterized by significant extracellular matrix (ECM) deposition. The specific cellular mediators that contribute to the development of fibrosis are not well understood. Using a model of fibrosis with Angiotensin II (AngII) infusion, our aim was to characterize the cellular elements involved in the development of myocardial fibrosis.

Antimycobacterial screening of traditional medicinal plants using the microplate resazurin assay.

Multidrug-resistant Mycobacterium tuberculosis strains have rapidly become a global health concern. North American First Nations communities have used traditional medicines for generations to treat many pulmonary infections. In this study, we evaluated the antimycobacterial activity of 5 medicinal plants traditionally used as general therapeutics for pulmonary illnesses and specifically as treatments for tuberculosis.

Neutrophil mediated smooth muscle cell loss precedes allograft vasculopathy.

Background: Cardiac allograft vasculopathy (AV) is a pathological process of vascular remodeling leading to late graft loss following cardiac transplantation. While there is consensus that AV is alloimmune mediated, and evidence that the most important alloimmune target is medial smooth muscle cells (SMC), the role of the innate immune response in the initiation of this disease is still being elucidated. As ischemia reperfusion (IR) injury plays a pivotal role in the initiation of AV, we hypothesize that IR enhances the early innate response to cardiac allografts.

Reduction in postsurgical adhesion formation after cardiac surgery by application of N,O-carboxymethyl chitosan.

Objective: The study objectives were to assess the efficacy of N,O carboxymethyl chitosan film in reducing postsurgical adhesion in a rabbit cardiac injury model and to confirm the efficacy of N,O carboxymethyl chitosan gel and film in reducing postsurgical adhesion formation in a pig cardiac injury model.

Methods: (1) Rabbit cardiac injury model: Cardiac injury was generated by abrading the anterior surface of the heart and desiccation with oxygen. N,O carboxymethyl chitosan solution and film were administered to the injured surface.

IFN-gamma and Fas/FasL pathways cooperate to induce medial cell loss and neointimal lesion formation in allograft vasculopathy.

Using a clinically relevant, fully disparate, allogeneic aortic transplant mouse model of allograft vasculopathy, we have demonstrated that neointimal proliferation is dependent on CD8(+) T cell effector pathways in the presence of therapeutic doses of calcineurin inhibitor (CNI) immunosuppression. CD4(+) T cell pathways are ablated by CNI immunosuppression. In the current study, we examined the relationship between CD8(+) T cell activities, medial SMC loss and neointimal hyperplasia.

Contribution of pre-existing vascular disease to allograft vasculopathy in a murine model.

Allograft vasculopathy (AV) has emerged as a major obstacle for long-term graft survival after cardiac transplantation. The shortage of donor hearts has meant fewer restrictions have been placed on acceptable hearts over the past few years resulting in an increase in the number of older hearts in the donor pool. This increase has subsequently led to the increase of donor hearts containing pre-existing disease.

Echinacea-induced macrophage activation.

Public interest in Echinacea is growing rapidly. Unfortunately, there is little scientific evidence to support claims of efficacy of this widely used botanical, and little information about potential mechanism of action. This study examines the ability of Echinacea to upregulate macrophage function and begins to elucidate the mechanism of Echinacea-induced macrophage activation.

Immunologic targets in the etiology of allograft vasculopathy: endothelium versus media.

The respective roles of the endothelium and the media as allo-immune targets in the generation of allograft vasculopathy (AV) have yet to be clearly defined. Although endothelial damage has been implicated in the progression of AV, evidence from mechanical vascular injury models suggests that medial injury may play a more dominant role. The overall objective of this research was to determine the relative importance of the endothelium versus the media as a target for immune injury and induction of AV.

CD8(+) T cells mediate aortic allograft vasculopathy under conditions of calcineurin immunosuppression: role of IFN-gamma and CTL mediators.

We have developed a model of aortic allograft vasculopathy (AV) that uses mouse strains that are fully disparate at Class I, Class II and minor histocompatibility antigens. Acute rejection is ablated with therapeutic doses of the calcineurin inhibitor Cyclosporine A (CyA). In this way we successfully mimic human disease.

CD8+ gammadelta T regulatory cells mediate kidney allograft prolongation after oral exposure to alloantigen.

The long term goal of immunological therapy for transplantation is to induce antigen specific unresponsiveness. One approach of significant current interest is the induction of T regulatory (Treg) cells that downregulate immune responses in an antigen specific manner. In this study, we examined the nature of the immunological regulation initiated by oral exposure to alloantigen.

Reduction in postsurgical adhesion formation after cardiac surgery in a rabbit model using N,O-carboxymethyl chitosan to block cell adherence.

Objective: The study objectives were to (1) assess the efficacy of N,O-carboxymethyl chitosan on postsurgical adhesion formation after cardiac surgery using a rabbit cardiac injury model and (2) explore the mechanism of action of N,O-carboxymethyl chitosan in the prevention of postsurgical adhesions using in vitro experimentation.

Methods: In the rabbit cardiac injury model, cardiac injury was generated by abrading the anterior surface of the heart with gauze and desiccated with oxygen. The rabbits were then either treated with N,O-carboxymethyl chitosan gel and solution on the injured surface or not treated.

Use of a sulfated chitosan derivative to reduce bladder inflammation in the rat.

Objectives: Interstitial cystitis is a chronic, debilitating disease of the bladder. Treatments using intravesicular inoculation of long-chain polysaccharide formulations, such as hyaluronic acid or anti-inflammatory agents, have been used to some effect. The objective of this study was to test a long-chain polysaccharide derivative of chitosan as a vehicle for delivery of the anti-inflammatory agent 5-aminosalicylic acid (5-ASA) for treatment of inflammation in the bladder.

Immunostimulant properties of Heracleum maximum Bartr.

The root of Heracleum maximum Bartr. (Umbelliferae), known to possess direct antifungal and anti-mycobacterial properties, has been reported anecdotally to possess antiviral properties. It was therefore hypothesized that the plant may have immunostimulant properties.

Aortic allograft vasculopathy is mediated by CD8(+) T cells in Cyclosporin A immunosuppressed mice.

We investigated the role of CD4(+) T cells and CD8(+) T cells in mediating allograft vasculopathy in Cyclosporin A (CyA) immunosuppressed mice. We first established that a dose of 50 mg/kg/d CyA was required to prevent acute rejection in C57BL/6 mice. CyA given at 50 mg/kg/d did not prevent allograft vasculopathy in either cardiac or aortic transplants in these mice.

Impairment of recipient cytolytic activity attenuates allograft vasculopathy.

We investigated the role of CD4+ and CD8+ T subsets as well as T cell cytolytic effector mechanisms in the aortic allograft model of allograft vasculopathy using CD4 and CD8 gene knockout mice (CD4(-/-), CD8(-/-)) and mice deficient in cytolytic effector pathways. Medial apoptosis at 2 weeks was reduced in CD8(-/-) mice and in mice where cytotoxic T cell activity was compromised. At 8 weeks, substantial medial damage was observed in wild-type (WT) and CD4(-/-) recipients but medial preservation was evident in CD8(-/-) mice and in mice with impaired cytotoxic T cell activity.

CD8+ T cells mediate aortic allograft vasculopathy by direct killing and an interferon-gamma-dependent indirect pathway.

Objective: Allograft vasculopathy (AV) has emerged as the major obstacle to long-term survival in clinical heart transplantation. Immune events are implicated in the development of AV, but the cellular and molecular mechanisms involved remain unclear. We sought to determine whether and by what mechanism CD8(+) T lymphocytes are able to generate AV in a murine aortic allograft model.