Osteopontin (OPN), a key component of the extracellular matrix, is associated with the fibrotic process during tissue remodeling. OPN and the cytokine interleukin (IL)-18 have been shown to be overexpressed in an array of human cardiac pathologies. In the present study, we determined the role of IL-18 in the regulation of cardiac OPN expression and the subsequent interstitial fibrosis and diastolic dysfunction. We demonstrated parallel increases in IL-18, OPN expression, and interstitial fibrosis in murine models of left ventricular pressure and volume overload. Exogenous recombinant (r)IL-18 administered for 2 wk increased cardiac OPN expression, interstitial fibrosis, and diastolic dysfunction. Stimulation of the T helper (Th)1 lymphocyte phenotype with a selective toll-like receptor (TLR)9 agonist induced cardiac IL-18 and OPN expression, which was associated with increased cardiac fibrillar collagen concentrations and interstitial fibrosis resulting in diastolic dysfunction. rIL-18 induced OPN expression and protein levels in primary of cardiac fibroblast cultures. Conditioned media from TLR9-stimulated T lymphocyte cultures induced IL-18 and OPN expression in cardiac fibroblasts, while blockade of the IL-18 receptor with a neutralizing antibody abolished the increase in OPN expression. Furthermore, a mutation in the transcriptional factor interferon regulatory factor (IRF)1 or IRF1 small interfering RNA (siRNA) resulted in the decreased expression of IL-18 and OPN in cardiac fibroblasts. With pressure overload, IRF1-mutant mice showed downregulation of IL-18 and OPN expression in cardiac tissue, reduced cardiac fibrotic development, and increased left ventricular function compared with wild type. These results provide direct evidence that the induction of IL-18 regulates OPN-mediated cardiac fibrosis and diastolic dysfunction. extracellular matrix; remodeling; T lymphocyte; interferon regulatory factor 1; toll-like receptor-9; lysyl oxidase LEFT VENTRICULAR REMODELING in response to pressure and/or volume overload is associated with myocardial hypertrophy, fibroblast hyperplasia, and increased concentrations of fibrillar collagen in the extracellular matrix. Recent studies have shown that pathological myocardial fibrosis may cause diastolic dysfunction and heart failure (24), whereas myocyte hypertrophy in the absence of fibrosis is considered physiological remodeling (22, 46) if the mass-to-volume ratio is preserved (5). In this study, we investigated whether interleukin (IL)-18 regulates the gene and protein expression of the matricellular protein osteopontin (OPN), a component and regulator of cardiac extracellular matrix fibrillar collagen concentrations.As reviewed by Okamoto (26), OPN also plays a critical role in the regulation of cellular proliferation and differentiation, interstitial fibrosis, arteriosclerosis, and angiogenesis. Although OPN is ubiquitously expressed in many tissues and is increased during stress-induced cardiac remodeling, it participates as a cytokine or humoral factor in the in...

Recently, the cytokine Interleukin-18 (IL-18) has been shown to be increased as a result of cardiac surgery. Elevated IL-18 has been associated with neurological dysfunction, systemic inflammatory response syndrome (SIRS), and multiple organ dysfunction syndrome (MODS) post open-heart surgery. The intent of the study contained herein was to determine the effect of IL-18 administration on cardiac function and structure. Eight C57BL/6 female mice were treated daily with 0.5microg/mouse of recombinant IL-18 for 7 days. Long axis echocardiography (ECHO) measurements of the anatomical and hemodynamic function of the heart for all mice were studied 24h after the last dose. The left ventricular wet weights increased from 84 +/- 1 to 93 +/- 3 mg when comparing the placebo (n = 8) with the IL-18 groups, respectively (p = 0.01). With ECHO analysis, IL-18 significantly increased left ventricular (LV) mass, the left atrium dimensions (LA), and the left ventricular posterior wall thickness (LVPW) over the 8-day time period (p < 0.01). There was a 5-fold increase in interstitial cardiac collagen content and a 30% increase in myocyte size in the IL-18 compared with the control groups (p < 0.01). Administration of IL-18 appears to induce interstitial fibrosis and myocyte hypertrophy, resulting in increased ventricular stiffness. Thus, increased IL-18 during and post open-heart surgical procedures may induce left ventricular diastolic dysfunction and affect post-operative outcomes.

Orbital and ocular adnexal lymphomas are rare and represent around 1-2% of lymphomas and about 8% of the extranodal lymphomas. However, these entities represent the majority of orbital malignancies. Lymphomas of the ocular adnexal region are primary or secondary lymphomas, and the majority of them are composed of small, mature lymphocytes, which provide a large differential diagnosis. Thus, these entities are not easily distinguished from indolent lymphoid processes such as reactive lymphoid hyperplasia. Extranodal marginal zone lymphoma is the most common lymphoma in the ocular adnexal region. However, this entity cannot be distinguished from benign lymphoid proliferations or other lymphomas composed of small, mature lymphocytes by routine histopathology. We describe a 78-year-old man who presents with bilateral upper eyelid masses, which had been present and grew in size over the past twelve months prior to his presentation. A biopsy of the mass shows a monotonous population of small, mature lymphocytes. The immunohistochemical studies performed on the eyelid mass confirmed a monoclonal proliferation of B cells expressing cyclin-D1; therefore, a final diagnosis of mantle cell lymphoma was rendered. A literature review of mantle cell lymphoma with orbital and ocular adnexal involvement and the diagnostic pitfalls in this area of hematopathology are discussed.

Most patients with cardiac disease have diastolic dysfunction which is characterized by impaired diastolic filling and/or abnormal diastolic relaxation. The trans-esophageal echocardiography (TEE) used routinely during open-heart surgical procedures has exceptional resolution that may permit the identification and grading of diastolic dysfunction. The goal of this study was to determine which echocardiography (ECHO) parameters can best describe diastolic dysfunction due to myocardial remodeling and fibrosis. Baseline transthoracic ECHO was performed on 3-month-old C57BL/6J female mice followed by administration of isoproterenol (2 microg/g/d) for 6 days. On day 7, transthoracic ECHO was performed to determine the change of left ventricular (LV) inflow parameters due to isoproterenol-mediated cardiac remodeling. The mid-LV region was stained with picrosirius red to quantify myocardial fibrosis and demonstrated a 5-fold increase in cardiac fibrosis (p = 0.002). LV mass was increased by 36% (p = 0.0016). Mitral valve flow Doppler peak velocities E and A were measured from a 4-chamber view. The E/A ratio did not change, but the E deceleration time, velocity time integral of the E-A complex (E-A VTI), E/E-A VTI ratio, isovolumic relaxation time (IVRT), and diastolic time all significantly increased. The corresponding tissue Doppler parameter, Ea/Aa ratio, decreased by 25% (p = 0.035). The left atrial dimension and the ECHO index of left atrial pressure (E/Ea) significantly increased (p < 0.02). These data suggest that, with a long-axis and a 4-chamber view, the clinician can adequately determine diastolic function in the open-heart surgical patient.

Intravascular large B-cell lymphoma (IVLBL) is a rare subtype of diffuse large B-cell lymphoma that resides in the lumen of blood vessels. Patients typically present with nonspecific findings, particularly bizarre neurologic symptoms, fever, and skin lesions. A woman presented with shortness of breath and a chest CT scan showed diffuse interstitial thickening and ground glass opacities suggestive of an interstitial lung disease. On physical exam she was noted to have splenomegaly. The patient died and at autopsy was found to have an IVLBL in her lungs as well as nearly all her organs that were sampled. Although rare, IVLBL should be included in the differential diagnosis of interstitial lung disease and this case underscores the importance of the continuation of autopsies.