Robert M Strieter

Background: Fibrocytes are bone marrow mesenchymal precursors with a surface phenotype compatible with leukocytes, fibroblasts, and hematopoietic progenitors that have been shown to traffic to wound healing sites in response to described chemokine pathways. Keloids are focal fibrotic responses to cutaneous trauma characterized by disordered collag...

Rhinovirus (RV) infections are a major cause of exacerbations in patients with asthma. Experimental RV challenges can provide insight into the pathophysiology of viral exacerbations. Previous reports, investigating mild or moderate asthma patients, have shown an upregulation in type 2 inflammation post RV infection, however, studies specifically in...

Key Points Fibrocytes are progenitor cells that home to injured organs and contribute to fibrosis. Levels of circulating fibrocytes are associated with pulmonary dysfunction in adults with SCD.

Half of the patients who present with unstable angina (UA) develop recurrent symptoms over the subsequent year. Identification of patients destined to develop such adverse events would be clinically valuable, but current tools do not allow for this discrimination. Fibrocytes are bone marrow-derived progenitor cells that co-express markers of leukoc...

Cyclooxygenase-2 (COX-2) the enzyme at the rate-limiting step of prostanoid production is over expressed in human lung cancer. Both COX-2 and its product prostaglandin (PG) E2 underlie molecular and cellular immunosuppressive networks that contribute to the pathogenesis of non–small cell lung cancer through immune tolerance and escape from host imm...

Background: A biomarker that predicts poor asthma control would be clinically useful. Fibrocytes are bone marrow-derived circulating progenitor cells that have been implicated in tissue fibrosis and TH2 responses in asthmatic patients. Objective: We sought to test the hypothesis that the concentration and activation state of peripheral blood fib...

Interstitial lung disease is common in patients with sickle cell anemia (SCA). Fibrocytes are circulating cells implicated in the pathogenesis of pulmonary fibrosis and airway remodeling in asthma. In this study, we tested the hypotheses that fibrocyte levels are: (1) increased in children with SCA compared to healthy controls, and (2) associated w...

Advancing drug development for airway diseases beyond the established mechanisms and symptomatic therapies requires redefining the classifications of airway diseases, considering systemic manifestations, developing new tools and encouraging collaborations.

Tumors are complex ecosystems composed of networks of interacting 'normal' and malignant cells. It is well recognized that cytokine-mediated cross-talk between normal stromal cells, including cancer-associated fibroblasts (CAFs), vascular endothelial cells, immune cells, and cancer cells, influences all aspects of tumor biology. Here we demonstrate...

CXC chemokines and their receptors (CXCR) influence the tumor microenvironment (TME) by regulating angiogenesis, recruiting activated immune cells and effecting tumor cell proliferation/metastases. CXCR3/ligand expression in tumors has divergent roles, either promoting or inhibiting tumor progression. These effects can be explained by the tumor CXC...

Bone marrow-derived endothelial progenitor cells (EPCs) contribute to neovessel formation in response to growth factors, cytokines, and chemokines. Chemokine receptor CXCR2 and its cognate ligands are reported to mediate EPC recruitment and angiogenesis. CXCR2 possesses a consensus PSD-95/DlgA/ZO-1 (PDZ) motif which has been reported to modulate ce...

Background: In patients with sickle cell disease (SCD), tissue injury due to vaso-occlusion can result in fibrosis and organ dysfunction. Fibrocytes are circulating bone marrow-derived cells that can home to damaged organs, differentiate into fibroblasts and myofibroblasts and contribute to scarring. Fibrocytes have been implicated in the pathogene...

Rationale: The rate of progression of most interstitial lung diseases (ILD) is unpredictable. Fibrocytes are circulating bone marrow-derived cells that have been implicated in the pathogenesis of lung fibrosis. Hermansky-Pudlak syndrome (HPS), a genetic cause of ILD in early adulthood, allows for study of biomarkers of ILD in a homogeneous populat...

Background: Eosinophilic esophagitis (EoE) is a chronic allergic disease with limited treatment options. Objective: We evaluated QAX576, an mAb against IL-13, in the treatment of patients with EoE. Methods: Patients (18-50 years) with proton pump inhibitor-resistant esophageal eosinophilia received intravenous QAX576 (6 mg/kg) or placebo (2:1)...

Unlabelled: Chemokines have been implicated as key contributors of non-small cell lung cancer (NSCLC) metastasis. However, the role of CXCR7, a recently discovered receptor for CXCL12 ligand, in the pathogenesis of NSCLC is unknown. To define the relative contribution of chemokine receptors to migration and metastasis, we generated human lung A549...

TPS3118^ Background: One mechanism to improve immunologic outcomes of vaccine therapy, and other immune therapies, is to optimize T cell trafficking to sites of tumor. CXCR3 is expressed by Th1 and Tc1 T cells and directs them to sites of inflammation by following the chemokine gradient. The ligands for CXCR3 (CXCL9 (MIG), CXCL10 (IP-10) and CXCL11...

10  Abstract— Lung cancer remains a challenging health problem with more than 1.1 million deaths worldwide annually. With current therapy, the long term survival for the majority of lung cancer patients remains low, thus new therapeutic strategies are needed. One such strategy would be to develop immune therapy for lung cancer. Immune approaches r...

Lung cancer remains a challenging health problem with more than 1.1 million deaths worldwide annually. With current therapy, the long term survival for the majority of lung cancer patients remains low, thus new therapeutic strategies are needed. One such strategy would be to develop immune therapy for lung cancer. Immune approaches remain attractiv...

Bone marrow-derived endothelial progenitor cells (EPCs) contribute to neovessel formation in response to various growth factors and cytokines. It has been reported that chemokine receptor CXCR2 and its cognate ligands mediate EPC recruitment and angiogenesis. CXCR2 possesses a consensus PDZ (PSD-95/DlgA/ZO-1) motif at their carboxyl termini, and th...

Myeloid derived suppressor cells (MDSC) are important regulators of immune responses. We evaluated the mechanistic role of MDSC depletion on antigen presenting cell (APC), NK, T cell activities and therapeutic vaccination responses in murine models of lung cancer. Individual antibody mediated depletion of MDSC (anti-Gr1 or anti-Ly6G) enhanced the a...

Unlabelled: Background: HMG-CoA reductase inhibitors (statins) have pleiotropic effects that are independent of cholesterol-lowering, including a dose-dependent effect on angiogenesis. Angiogenesis plays a critical role both in vascularization of the chronically ischemic myocardium and in stabilization of atherosclerotic plaques. Chemokines, a f...

Background and purpose: The chemokine ligand CXCL12 is constitutively expressed in the bone marrow and other tissues including the brain endothelium and is responsible for regulating the trafficking of bone marrow progenitor cells. CXCL12 has been shown to play a significant role in animal models of ischemic stroke but its role in human stroke is...

Lung cancer evades host immune surveillance by dysregulating inflammation. Tumors and their surrounding stromata produce growth factors, cytokines, and chemokines that recruit, expand, and/or activate myeloid-derived suppressor cells (MDSCs). MDSCs regulate immune responses and are frequently found in malignancy. In this review the authors discuss...

The specific mechanisms that mediate CD4(+) T-cell-mediated liver injury have not been fully elucidated. CD4(+) invariant natural killer T (iNKT) cells are required for liver damage in some mouse models of hepatitis, while the chemokine receptors CXCR3 and CCR5 are considered dominant Th1 chemokine receptors involved in Th1 trafficking in inflammat...

Autopsy and biopsy studies have shown that there is significantly more fibrosis in hearts of patients with hypertensive heart disease compared to normal hearts. Fibrocytes, a population of circulating bone marrow-derived cells, have been shown to home to tissues and promote scar formation in several diseases, but their role in human hypertensive he...

Fibrosis is fundamental to the pathogenesis of many chronic lung diseases, including some lung infections, airway diseases such as bronchiectasis and asthma, and most of the diffuse parenchymal lung diseases. Idiopathic pulmonary fibrosis, the prototypical fibrotic lung disease, is amongst the most common diffuse parenchymal lung diseases and is ch...

Perivascular infiltrating mononuclear cells have been described in the vasculopathy found in multiple types of pulmonary arterial hypertension (PAH). We determined the expression of a specific type 1 immune response cytokine-chemokine cascade-interleukin (IL)-18 → (monokine induced by γ-interferon [MIG]/chemokine [C-X-C motif] ligand [CXCL] 9, inte...

Despite many recent advances in the field, the underlying mechanisms governing pulmonary fibrosis remain poorly understood. We have used an experimental system of fibrotic granuloma development via the embolization of Schistosoma mansoni eggs to the lungs. Egg embolization results in the release of highly antigenic glycoproteins (Schistosoma egg an...

Interstitial lung disease is a frequent complication in sickle cell disease and is characterized by vascular remodeling and interstitial fibrosis. Bone marrow-derived fibrocytes have been shown to contribute to the pathogenesis of other interstitial lung diseases. The goal of this study was to define the contribution of fibrocytes to the pathogenes...

Detailed Methods section. (DOC)

The tumor microenvironment is extremely complex and depends on tumor cell interaction with the responding host cells. Angiogenesis, or new blood vessel growth from pre-existing vasculature, is a preeminent feature of successful tumor growth of all solid tumors. While a number of factors produced by both the tumor cells and host responding cells hav...

The accumulation of high levels of adenosine in tumors activates A(2A) and A(2B) receptors on immune cells and inhibits their ability to suppress tumor growth. Deletion of adenosine A(2A) receptors (A(2A)ARs) has been reported to activate antitumor T cells, stimulate dendritic cell (DC) function, and inhibit angiogenesis. In this study, we evaluate...

Chemokines are a family of chemotactic cytokines that function in host defense by orchestrating cellular movement during infection. In addition to this function, many chemokines have also been found to mediate the direct killing of a range of pathogenic microorganisms through an as-yet-undefined mechanism. As an understanding of the molecular mecha...

Development of bronchiolitis obliterans syndrome (BOS) after lung transplantation confers increased patient morbidity and mortality. Fibrocytes are circulating bone marrow-derived mesenchymal cell progenitors that influence tissue repair and fibrosis. Fibrocytes have been implicated in chronic pulmonary inflammatory processes. We investigated the c...

The recruitment of specific leukocyte subpopulations in response to lung injury is a fundamental mechanism of acute pulmonary inflammation. The elicitation of leukocytes is dependent upon a complex series of events, including reduced leukocyte deformability, endothelial cell activation and expression of endothelial cell-derived leukocyte adhesion m...

In patients with chronic ischemic heart disease (IHD), the presence and extent of spontaneously visible coronary collaterals are powerful determinants of clinical outcome. There is marked heterogeneity in the recruitment of coronary collaterals amongst patients with similar degrees of coronary artery stenoses, but the biological basis of this heter...

Neutrophils are essential for successful host eradication of bacterial pathogens and for survival to polymicrobial sepsis. During inflammation, the bone marrow provides a large reserve of neutrophils that are released into the peripheral circulation where they traverse to sites of infection. Although neutrophils are essential for survival, few stud...

We evaluated the utility of chimeric γc homeostatic cytokine, IL-7/IL-7Rα-Fc, to restore host APC (antigen presenting cell) and T cell activities in lung cancer. Utilizing murine lung cancer models we determined the antitumor efficacy of IL-7/IL-7Rα-Fc. APC, T cell, cytokine analyses, neutralization of CXCL9, CXCL10, and IFNγ were carried out to ev...

Pulmonary sarcoidosis involves an intense leukocyte infiltration of the lung with the formation of non-necrotizing granulomas. CC chemokines (chemokine (C-C motif) ligand 2 (CCL2)-CCL5) are chemoattractants of mononuclear cells and act through seven transmembrane G-coupled receptors. Previous studies have demonstrated conflicting results with regar...

Epithelial neutrophil-activating peptide-78 (CXCL5), a member of the CXC chemokine family, has been shown to be involved in angiogenesis, tumor growth, and metastasis. The objective of this study was to determine the relationship between CXCL5 expression and tumor progression in human pancreatic cancer and to elucidate the mechanism underlying CXCL...

Fibrosis is the end result of a complex series of events that follow tissue injury and inflammation. Pathophysiologic fibrosis results in permanent scar formation, and can impair organ function. Fibrocytes are circulating, bone-marrow-derived progenitor cells that traffic from the bone marrow to the injured organ via the bloodstream, where they dif...

The prototypic interstitial lung disease, idiopathic pulmonary fibrosis (IPF), is a progressive fibrotic illness with no effective therapy that typically results in respiratory failure. This chapter reviews the data on the role of the family of chemokine ligands and receptors in mediating vascular remodeling and in orchestrating the recruitment of...

The tumor microenvironment is extremely complex that depends on tumor cell interaction with the responding host cells. Angiogenesis, or new blood vessel growth from preexisting vasculature, is a preeminent feature of successful tumor growth of all solid tumors. While a number of factors produced by both the tumor cells and host responding cells hav...

CXCR3 neutralizing serum significantly reduces host cell infiltration in response to CXCL9, CXCL10, and CXCL11 in vivo. C57BL/6 mice (n = 5 per group) received no injection (untreated) or an i.p. injection of control serum or CXCR3 neutralizing serum. Subsequently, animals received mouse serum albumin (-) or 10 ng total of each CXCL9, CXCL10, and C...

CXCR3 neutralization does not disrupt CXC chemokine induction in response to B. anthracis spore challenge. Lung tissue (n = 5-6 animals per group per time point) was harvested from naà ^ve C57BL/6 mice (untreated) or spore-challenged animals receiving control serum or CXCR3 neutralizing serum. ELISA quantification is expressed as median (interquart...

CXCL9-mediated direct antimicrobial effects against B. anthracis Sterne strain spores and bacilli are concentration dependent. B. anthracis spores (A and B) or bacilli (C and D) were treated with increasing amounts of murine CXCL9 for 6 h before end point determination, n = 3 independent experiments. Alamar Blue analysis demonstrated concentration-...

Inflammatory cell populations present in the lungs of spore-challenged mice receiving CXCL9/CXCL10/CXCL11 or CXCR3 neutralizing sera are equivalent. Two days post-challenge, single cell suspensions were prepared from the lungs of C57BL/6 mice (n = 4 animals per group) receiving neutralizing or control serum. Host cell populations were analyzed by f...

Chemokines have been found to exert direct, defensin-like antimicrobial activity in vitro, suggesting that, in addition to orchestrating cellular accumulation and activation, chemokines may contribute directly to the innate host response against infection. No observations have been made, however, demonstrating direct chemokine-mediated promotion of...

Immune-mediated cancer regression requires tumor infiltration by antigen-specific effector T cells, but lymphocytes are commonly sparse in melanoma metastases. Activated T cells express CXCR3, whose cognate chemokines are CXCL9/MIG, CXCL10/IP-10, and CXCL11/I-TAC. Little is known about expression of these chemokines in lymph node (LN) metastases of...

Current understanding of specific defense mechanisms in the context of neutropenic infections is limited. It has previously been reported that invasive aspergillosis, a prototypic opportunistic infection in neutropenic hosts, is associated with marked accumulation of inflammatory dendritic cells (DCs) in the lungs. Given recent data indicating that...

We investigated possible cellular receptors for the human CXC chemokine platelet factor-4 variant/CXCL4L1, a potent inhibitor of angiogenesis. We found that CXCL4L1 has lower affinity for heparin and chondroitin sulfate-E than platelet factor-4 (CXCL4) and showed that CXCL10 and CXCL4L1 could displace each other on microvascular endothelial cells....

Chemokines are a superfamily of structurally homologous heparin-binding proteins that influence tumor growth and metastasis. Several members of the CXC and CC chemokine families are potent inducers of neovascularization, whereas a subset of the CXC chemokines are potent inhibitors. In this paper, we review the current literature regarding the role...

Regeneration and fibrosis are integral parts of the recovery from tissue injury, and impaired regulation of these mechanisms is a hallmark of many chronic diseases. Traditionally, resident tissue fibroblasts have been thought to proliferate and mediate local fibrosis. However, more recently, data suggest that a circulating bone-marrow-derived proge...

Multiple sclerosis (MS) is a human demyelinating disease characterized by multifocal regions of inflammation, progressive myelin loss within the central nervous system (CNS), and eventual failure to remyelinate damaged axons. These problems suggest deficiencies in recruiting and/or maturation of oligodendrocyte progentior cells (OPCs) and highlight...

Fibrocytes are bone marrow-derived cells. Fibrocytes can differentiate into adipocyte- and myofibroblast-like cells. Since fibrocytes can behave like mesenchymal progenitor cells, we hypothesized that fibrocytes have the potential to differentiate into other mesenchymal lineage cells, such as osteoblasts and chondrocytes. In this study, we found th...

Immune-mediated cancer regression requires tumor infiltration by Ag-specific effector T cells, but lymphocytes are commonly sparse in melanoma metastases. Activated T cells express CXCR3, whose cognate chemokines are CXCL9/MIG, CXCL10/IP-10 and CXCL11/I-TAC. Little is known about expression of these chemokines in lymph node (LN) metastases of melan...

Here we investigate the dynamics of the hepatic intravascular immune response to a pathogen relevant to invariant natural killer T cells (iNKT cells). Immobilized Kupffer cells with highly ramified extended processes into multiple sinusoids could effectively capture blood-borne, disseminating Borrelia burgdorferi, creating a highly efficient survei...