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Biomedical subjects

Robert M Strieter

Publications and source records attributed to Robert M Strieter.

At least 91 records · Page 5Linked to original sources
PubMed2003

The C-X-C chemokine IP-10 stimulates HIV-1 replication.

Chemokines play critical roles in HIV-1 infection, serving both to modulate viral replication and to recruit target cells to sites of infection. Interferon-gamma-inducible protein 10 (IP-10/CXCL10) is a C-X-C chemokine that acts specifically upon activated T cells and macrophages and attracts T cells into the cerebrospinal fluid (CSF) in HIV-associated neurological disease. We now demonstrate that IP-10 stimulates HIV-1 replication in monocyte-derived macrophages and peripheral blood lymphocytes. We further demonstrate that neutralization of endogenous IP-10 or blocking the function of its receptor, CXCR3, reduces HIV-1 replication in these same cells. Therefore, blocking the interaction between IP-10 and CXCR3 represents a possible new target for anti-retroviral therapy.

Cell Adhesion↗
PubMed2003

Differential effects of Sendai virus infection on mediator synthesis by mesangial cells from two mouse strains.

BACKGROUND: Recently, we observed that the severity of glomerulonephritis in an experimental model of immunoglobulin A nephropathy (IgAN) induced by Sendai virus differs between C57BL/6 and BALB/c mouse strains. The determinants of differing renal insufficiency are not understood. In the present study, we examine the capacity for mesangial cells to support Sendai viral replication and assess the direct effects of Sendai virus on the production of selected cytokines, chemokines, and eicosanoids by mesangial cells, comparing C57BL/6 to BALB/c mouse strains. METHODS: Sendai virus replication was measured by viral plaque assay using LLCMK2 cells. Production of cytokines [interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha)], chemokines (JE and KC), and eicosanoids [prostaglandin E2 (PGE2) and thromboxane B2 (TxB2)] in culture medium was evaluated by sandwich enzyme-linked immunosorbent assay (ELISA) or competitive enzyme immunoassay (EIA) after 48 hours' incubation with infectious or inactivated Sendai virus. RESULTS: Sendai virus replicates equally well in mesangial cells from both strains, and infection evokes increased IL-6, JE, KC, and PGE2 production in relation to viral dose. BALB/c mesangial cells produce significantly more IL-6 and JE than those from C57BL/6, and the dose response for KC is steeper in BALB/c mesangial cells than those from C57BL/6. Synthesis of PGE2 in BALB/c mesangial cells is higher than that of C57BL/6 mesangial cells, both under basal conditions and in response to infectious Sendai virus, again in a dose-dependent manner. There is no TNF-alpha or thromboxane response to viral stimulation. CONCLUSION: We conclude that different mesangial cell responses to this common mucosal viral pathogen might influence the severity of IgAN in our model system.

Animals↗
PubMed2003

Bronchiolitis obliterans syndrome complicating lung or heart-lung transplantation.

Lung transplantation is a therapeutic option for patients with end stage lung diseases, but long-term survival remains poor, primarily due to chronic allograft rejection. Bronchiolitis obliterans (BO), a fibrotic process resulting in progressive narrowing of bronchiolar lumens and airflow obstruction, is a manifestation of chronic allograft rejection. The term obliterative bronchiolitis ( OB) is synonymous. Once bronchiolitis obliterans syndrome (BOS) develops, progressive decline in pulmonary function is typical; most patients die of respiratory failure within 5 years of onset. The diagnosis of BOS is usually made by clinical, physiological, and radiographic parameters. The dominant risk factor for BOS is acute allograft rejection, but additional factors play contributory roles [e.g., infections; human leukocyte antigen (HLA) mismatching; and injury to the allograft or airways]. The pathogenesis of BOS is complex and involves myriad cell types (both immune and nonimmune) and release of diverse cytokines and chemokines. Unfortunately, current therapies for BOS are of unproven value. A greater understanding of the pathogenic mechanisms operative in BOS are critical to developing novel strategies to treat and prevent this devastating complication.

Journal Article↗
PubMed2003

Host innate defenses in the lung: the role of cytokines.

PURPOSE OF REVIEW: The lung has a unique relationship with the environment. Through evolution the lung has developed strategies to defend itself from microbial invasion. As we encounter increasing multidrug-resistant microorganisms, we need to further our knowledge of innate defense systems in order to design novel strategies to deal with these microbes without inducing over-exuberant inflammation and lung injury. RECENT FINDINGS: The development of lung innate immunity requires microbial molecular pattern recognition by the recently described Toll like receptors, the release of early response cytokines that further activate the 'master switch', nuclear factor-kappaB, leading to amplified host defense to invading microbes. A balance of Type 1 and Type 2 cytokines modulates the intensity of innate immunity. Cytokines/chemokines orchestrate the polarization and transition of innate to adaptive immunity. SUMMARY: The elucidation of the pathways involved in innate immunity and factors controlling the transition to adaptive immunity will improve our understanding of the host response to infection and improve our ability to design new therapies for the treatment of infectious disease.

Chemokines↗
PubMed2002

Imbalance in the expression of CXC chemokines correlates with bronchoalveolar lavage fluid angiogenic activity and procollagen levels in acute respiratory distress syndrome.

Diffuse alveolar damage is the histopathological hallmark of acute respiratory distress syndrome (ARDS) and is a stereotypic response to a variety of etiologies. Moreover, a significant proportion of ARDS survivors have residual pulmonary fibrosis and compromised pulmonary function. This suggests that the pathogenesis of diffuse alveolar damage that ultimately leads to the chronic fibrosis of ARDS has features of dysregulated repair exemplified by exaggerated intra-alveolar angiogenesis and fibrogenesis (i.e., fibroproliferation and deposition of extracellular matrix), leading to progressive alveolar fibrosis and impaired lung function. We obtained bronchoalveolar lavage fluid (BALF) from patients with ARDS or ventilated control patients and assessed CXC chemokine levels by ELISA. We found an imbalance in the expression of ELR(+) as compared with ELR(-) CXC chemokines from BALF of patients with ARDS as compared with controls. This imbalance correlated with angiogenic activity as assessed by the corneal micropocket assay. Furthermore, these levels correlated with both procollagen I and procollagen III levels in BALF. In contrast, while BALF levels of vascular endothelial growth factor were elevated, vascular endothelial growth factor did not appear to be significantly contributing to the angiogenic activity. These findings suggest that CXC chemokines have an important role in the fibroproliferative phase of ARDS via the regulation of angiogenesis.

Amino Acid Motifs↗
PubMed2002

Critical role for CXCR3 chemokine biology in the pathogenesis of bronchiolitis obliterans syndrome.

Bronchiolitis obliterans syndrome (BOS) is the major limitation to survival post-lung transplantation and is characterized by a persistent peribronchiolar inflammation that eventually gives way to airway fibrosis/obliteration. Acute rejection is the main risk factor for the development of BOS and is characterized by a perivascular/bronchiolar leukocyte infiltration. The specific mechanism(s) by which these leukocytes are recruited have not been elucidated. The CXC chemokines (monokine induced by IFN-gamma (MIG)/CXC chemokine ligand (CXCL)9, IP-10/CXCL10, and IFN-inducible T cell alpha chemoattractant (ITAC)/CXCL11) act through their shared receptor, CXCR3. Because they are potent leukocyte chemoattractants and are involved in other inflammation/fibroproliferative diseases, we hypothesized that the expression of these chemokines during an allogeneic response promotes the persistent recruitment of mononuclear cells, leading to chronic lung rejection. We found that elevated levels of MIG/CXCL9, IFN-inducible protein 10 (IP-10)/CXCL10, and ITAC/CXCL11 in human bronchoalveolar lavage fluid were associated with the continuum from acute to chronic rejection. Translational studies in a murine model demonstrated increased expression of MIG/CXCL9, IP-10/CXCL10, and ITAC/CXCL11 paralleling the recruitment of CXCR3-expressing mononuclear cells. In vivo neutralization of CXCR3 or its ligands MIG/CXCL9 and IP-10/CXCL10 decreased intragraft recruitment of CXCR3-expressing mononuclear cells and attenuated BOS. This supports the notion that ligand/CXCR3 biology plays an important role in the recruitment of mononuclear cells, a pivotal event in the pathogenesis of BOS.

Animals↗
PubMed2002

Interleukin-1 receptor antagonist as a biomarker for bronchiolitis obliterans syndrome in lung transplant recipients.

BACKGROUND: The major limitation to survival after lung transplantation is bronchiolitis obliterative syndrome (BOS). BOS is a chronic inflammatory/immunologic process characterized by fibroproliferation, matrix deposition, and obliteration of the airways. The mechanism(s) that lead to fibro-obliteration of allograft airways have not been fully elucidated. Interleukin-1 receptor antagonist (IL-1Ra) is a naturally occurring antagonist of the pro-inflammatory cytokine IL-1 and has been associated with a number of fibroproliferative diseases. METHODS: We determined whether IL-1Ra, as compared to IL-1beta, IL-10, transforming growth factor (TGF)-beta, and tumor necrosis factor (TNF)-alpha, in the bronchoalveolar lavage fluid (BALF) from lung transplant recipients was associated with BOS. BALF was collected from three groups of patients: BOS (n=22), acute rejection (n=33), and healthy transplant recipients (n=30). RESULTS: IL-1Ra levels were significantly elevated in patients with BOS compared to healthy lung transplant recipients and patients with acute rejection (P<0.001 and P<0.05, respectively). Furthermore, when patients with BOS had their BALF analyzed from their last bronchoscopy before the development of BOS (Future BOS [FBOS] group) (n=20), their levels of IL-1Ra were also significantly elevated compared to healthy lung transplant recipients and patients with acute rejection (P<0.001 and P<0.05, respectively). Importantly, the elevated levels of IL-1Ra in the BOS and FBOS groups were not accompanied by any significant increases in IL-1beta, IL-10, TGF-beta, or TNF-alpha. CONCLUSION: These findings suggest that elevated levels of IL-1Ra may be attenuating IL-1 bioactivity during the pathogenesis of BOS and creating a local environment that favors fibroproliferation and matrix deposition.

Acute Disease↗
PubMed2002

The role of MIG/CXCL9 in cardiac allograft vasculopathy.

T lymphocytes play a critical role in chronic rejection of transplanted hearts, or cardiac allograft vasculopathy (CAV). However, the molecular mediators of T lymphocyte recruitment in CAV are incompletely defined. We hypothesized that the chemokine, monokine induced by interferon-gamma (MIG/CXCL9), which induces T lymphocyte migration in vitro, participates in T lymphocyte recruitment in CAV. In a previously characterized MHC II-mismatched murine model of CAV, intragraft MIG/CXCL9 gene transcript and protein levels increased on days 7, 14, and 24 days after transplantation, paralleling T lymphocyte recruitment and preceding intimal thickening. Antibody neutralization of MIG/CXCL9 significantly reduced CD4(+) T lymphocyte infiltration and intimal thickening in this model. MIG/CXCL9 was produced by graft-infiltrating MOMA-2+ macrophages in early and late stages of CAV. And, although T lymphocytes did not produce MIG/CXCL9, recipient CD4(+) T lymphocytes were required for sustained intragraft MIG/CXCL9 production and CAV development. These findings demonstrate that 1) MIG/CXCL9 plays an important role in CD4(+) T lymphocyte recruitment and development of CAV, 2) MOMA-2+ macrophages are the predominant recipient-derived source of MIG/CXCL9, and 3) recipient CD4 lymphocytes are necessary for sustained MIG/CXCL9 production and CAV development in this model. Neutralization of the chemokine MIG/CXCL9 may have therapeutic potential for the treatment of chronic rejection after heart transplantation.

Animals↗
PubMed2002

Multiple sclerosis: a study of CXCL10 and CXCR3 co-localization in the inflamed central nervous system.

T-cell accumulation in the central nervous system (CNS) is considered crucial to the pathogenesis of multiple sclerosis (MS). We found that the majority of T cells within the cerebrospinal fluid (CSF) compartment expressed the CXC chemokine receptor 3 (CXCR), independent of CNS inflammation. Quantitative immunohistochemistry revealed continuous accumulation of CXCR3+ T cells during MS lesion formation. The expression of one CXCR3 ligand, interferon (IFN)-gamma-inducible protein of 10 kDa (IP-10)/CXC chemokine ligand (CXCL) 10 was elevated in MS CSF, spatially associated with demyelination in CNS tissue sections and correlated tightly with CXCR3 expression. These data suggest a critical role for CXCL10 and CXCR3 in the accumulation of T cells in the CNS of MS patients.

Adult↗
PubMed2002

Beta-chemokines are induced by Mycobacterium tuberculosis and inhibit its growth.

Chemokines (CK) are potent leukocyte activators and chemoattractants and aid in granuloma formation, functions critical for the immune response to Mycobacterium tuberculosis. We hypothesized that infection of alveolar macrophages (AM) with different strains of M. tuberculosis elicits distinct profiles of CK, which could be altered by human immunodeficiency virus (HIV) infection. RANTES, macrophage inflammatory protein-1 alpha (MIP-1 alpha), and MIP-1 beta were the major beta-CK produced in response to M. tuberculosis infection. Virulent M. tuberculosis (H37Rv) induced significantly less MIP-1 alpha than did the avirulent strain (H37Ra), while MIP-1 beta and RANTES production was comparable for both strains. MIP-1 alpha and MIP-1 beta were induced by the membrane, but not cytosolic, fraction of M. tuberculosis. M. tuberculosis-induced CK secretion was partly dependent on tumor necrosis factor alpha (TNF-alpha). AM from HIV-infected individuals produced less TNF-alpha and MIP-1 beta than did normal AM in response to either M. tuberculosis strain. We tested the functional significance of decreased beta-CK secretion by examining the ability of beta-CK to suppress intracellular growth of M. tuberculosis. MIP-1 beta and RANTES suppressed intracellular growth of M. tuberculosis two- to threefold, a novel finding. Thus, beta-CK contribute to the innate immune response to M. tuberculosis infection, and their diminution may promote the intracellular survival of M. tuberculosis.

Chemokine CCL4↗
PubMed2002

Interleukin-8 and growth-regulated oncogene alpha mediate angiogenesis in Kaposi's sarcoma.

The development of the complex neoplasm Kaposi's sarcoma is dependent on infection with the Kaposi's sarcoma-associated herpesvirus (KSHV) and appears to be greatly enhanced by cytokines and human immunodeficiency virus type 1 (HIV-1) Tat. Interleukin-8 (IL-8) and growth-regulated oncogene alpha (GRO-alpha) are chemokines involved in chemoattraction, neovascularization, and stimulation of HIV-1 replication. We have previously demonstrated that production of GRO-alpha is stimulated by exposure of monocyte-derived macrophages (MDM) to HIV-1. Here we show that exposure of MDM to HIV-1, viral Tat, or viral gp120 leads to a substantial increase in IL-8 production. We also demonstrate that IL-8 and GRO-alpha are induced by KSHV infection of endothelial cells and are crucial to the angiogenic phenotype developed by KSHV-infected endothelial cells in cell culture and upon implantation into SCID mice. Thus, the three known etiological factors in Kaposi's sarcoma pathogenesis-KSHV, HIV-1 Tat, and cellular growth factors-might be linked, in part, through induction of IL-8 and GRO-alpha.

Animals↗
PubMed2002

IL-7 inhibits fibroblast TGF-beta production and signaling in pulmonary fibrosis.

Based on studies by our group and others, we hypothesized that IL-7 may possess antifibrotic activities in an IFN-gamma-dependent and independent manner. Here, we have evaluated the antifibrotic therapeutic potential of IL-7 in both in vitro and in vivo pulmonary fibrosis models. IL-7 inhibited both TGF-beta production and signaling in fibroblasts and required an intact JAK1/STAT1 signal transduction pathway. IL-7-mediated inhibition of TGF-beta signaling was found to be associated with an increase in Smad7, a major inhibitory regulator in the SMAD family. In the presence of IL-7, Smad7 dominant negative fibroblasts restored TGF-beta-induced collagen synthesis, indicating that an IL-7-mediated increase in Smad7 suppressed TGF-beta signaling. Consistent with these in vitro findings, recombinant IL-7 decreased bleomycin-induced pulmonary fibrosis in vivo, independent of IFN-gamma. The antifibrotic activities of IL-7 merit further basic and clinical investigation for the treatment of pulmonary fibrosis.

Animals↗