Involvement of a ferroprotein sensor in hypoxia-mediated inhibition of neutrophil apoptosis

Blood ◽  
2002 ◽  
Vol 100 (8) ◽  
pp. 3008-3016 ◽  
Author(s):  
Katy I. Mecklenburgh ◽  
Sarah R. Walmsley ◽  
Andrew S. Cowburn ◽  
Michael Wiesener ◽  
Benjamin J. Reed ◽  
...  
Keyword(s):  
Oxygen Sensing ◽  
Hypoxia Inducible Factor ◽  
Glucose Deprivation ◽  
Cell Types ◽  
Human Neutrophils ◽  
Neutrophil Apoptosis ◽  
Low Oxygen ◽  
Sensing Mechanism ◽  
Survival Effect

Neutrophil apoptosis represents a major mechanism involved in the resolution of acute inflammation. In contrast to the effect of hypoxia observed in many other cell types, oxygen deprivation, as we have shown, causes a profound but reversible delay in the rate of constitutive apoptosis in human neutrophils when aged in vitro. This effect was mimicked by exposing cells to 2 structurally unrelated iron-chelating agents, desferrioxamine (DFO) and hydroxypyridines (CP-94), and it appeared specific for hypoxia in that no modulation of apoptosis was observed with mitochondrial electron transport inhibitors, glucose deprivation, or heat shock. The involvement of chelatable iron in the oxygen-sensing mechanism was confirmed by the abolition of the DFO and CP-94 survival effect by Fe2+ ions. Although hypoxia inducible factor-1α (HIF-1α) mRNA was identified in freshly isolated neutrophils, HIF-1α protein was only detected in neutrophils incubated under hypoxic conditions or in the presence of DFO. Moreover, studies with cyclohexamide demonstrated that the survival effect of hypoxia was fully dependent on continuing protein synthesis. These results indicate that the neutrophil has a ferroprotein oxygen-sensing mechanism identical to that for erythropoietin regulation and results in HIF-1α up-regulation and profound but reversible inhibition of neutrophil apoptosis. This finding may have important implications for the resolution of granulocytic inflammation at sites of low-oxygen tension.

scholarly journals Pseudomonas expression of an oxygen sensing prolyl hydroxylase homologue regulates neutrophil host responses in vitro and in vivo

2017 ◽  
Vol 2 ◽  
pp. 104 ◽  
Author(s):  
Rebecca S. Dickinson ◽  
Fiona Murphy ◽  
Catherine Doherty ◽  
Sam Williams ◽  
Ananda Mirchandani ◽  
...  
Keyword(s):  
Active Sites ◽  
Hypoxia Inducible Factor ◽  
Elongation Factor ◽  
Prolyl Hydroxylase ◽  
Human Neutrophils ◽  
Neutrophil Apoptosis ◽  
Wild Type ◽  
Prolyl Hydroxylases

Background: Pseudomonas species are adapted to evade innate immune responses and can persist at sites of relative tissue hypoxia, including the mucus-plugged airways of patients with cystic fibrosis and bronchiectasis.  The ability of these bacteria to directly sense and respond to changes in local oxygen availability is in part consequent upon expression of the 2-oxoglutarate oxygenase, Pseudomonas prolyl hydroxylase (PPHD), which acts on elongation factor Tu (EF-Tu), and is homologous with the human hypoxia inducible factor (HIF) prolyl hydroxylases. We report that PPHD expression regulates the neutrophil response to acute pseudomonal infection. Methods: In vitro co-culture experiments were performed with human neutrophils and PPHD-deficient and wild-type bacteria and supernatants, with viable neutrophil counts determined by flow cytometry. In vivo consequences of infection with PPHD deficient P. aeruginosa were determined in an acute pneumonia mouse model following intra-tracheal challenge. Results: Supernatants of PPHD-deficient bacterial cultures contained higher concentrations of the phenazine exotoxin pyocyanin and induced greater acceleration of neutrophil apoptosis than wild-type PAO1 supernatants in vitro.  In vivo infection with PPHD mutants compared to wild-type PAO1 controls resulted in increased levels of neutrophil apoptosis and impaired control of infection, with higher numbers of P. aeruginosa recovered from the lungs of mice infected with the PPHD-deficient strain.  This resulted in an overall increase in mortality in mice infected with the PPHD-deficient strain. Conclusions: Our data show that Pseudomonas expression of its prolyl hydroxylase influences the outcome of host-pathogen interactions in vitro and in vivo, demonstrating the importance of considering how both host and pathogen adaptations to hypoxia together define outcomes of infection. Given that inhibitors for the HIF prolyl hydroxylases are in late stage trials for the treatment of anaemia and that the active sites of PPHD and human HIF prolyl hydroxylases are closely related, the results are of current clinical interest.

scholarly journals Sequence and functional characterization of hypoxia-inducible factors, HIF1α, HIF2αa, and HIF3α, from the estuarine fish, Fundulus heteroclitus

2017 ◽  
Vol 312 (3) ◽  
pp. R412-R425 ◽  
Author(s):  
Ian K. Townley ◽  
Sibel I. Karchner ◽  
Elena Skripnikova ◽  
Thomas E. Wiese ◽  
Mark E. Hahn ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Fundulus Heteroclitus ◽  
Phylogenetic Analyses ◽  
Functional Characterization ◽  
Hypoxia Inducible Factor ◽  
Estuarine Fish ◽  
Low Oxygen ◽  
Aryl Hydrocarbon ◽  
Transactivation Domains

The hypoxia-inducible factor (HIF) family of transcription factors plays central roles in the development, physiology, pathology, and environmental adaptation of animals. Because many aquatic habitats are characterized by episodes of low dissolved oxygen, fish represent ideal models to study the roles of HIF in the response to aquatic hypoxia. The estuarine fish Fundulus heteroclitus is found in habitats prone to hypoxia. It responds to low oxygen via behavioral, physiological, and molecular changes, and one member of the HIF family, HIF2α, has been previously described. Herein, cDNA sequencing, phylogenetic analyses, and genomic approaches were used to determine other members of the HIFα family from F. heteroclitus and their relationships to HIFα subunits from other vertebrates. In vitro and cellular approaches demonstrated that full-length forms of HIF1α, HIF2α, and HIF3α independently formed complexes with the β-subunit, aryl hydrocarbon receptor nuclear translocator, to bind to hypoxia response elements and activate reporter gene expression. Quantitative PCR showed that HIFα mRNA abundance varied among organs of normoxic fish in an isoform-specific fashion. Analysis of the F. heteroclitus genome revealed a locus encoding a second HIF2α—HIF2αb—a predicted protein lacking oxygen sensing and transactivation domains. Finally, sequence analyses demonstrated polymorphism in the coding sequence of each F. heteroclitus HIFα subunit, suggesting that genetic variation in these transcription factors may play a role in the variation in hypoxia responses among individuals or populations.

scholarly journals Hypoxia-Inducible Factor 1α Is Essential for Cell Cycle Arrest during Hypoxia

2003 ◽  
Vol 23 (1) ◽  
pp. 359-369 ◽  
Author(s):  
Nobuhito Goda ◽  
Heather E. Ryan ◽  
Bahram Khadivi ◽  
Wayne McNulty ◽  
Robert C. Rickert ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Transcription Factor ◽  
Cell Cycle Arrest ◽  
Cellular Response ◽  
Hypoxia Inducible Factor ◽  
Growth Arrest ◽  
Cell Types ◽  
Low Oxygen ◽  
Double Knockout ◽  
Cycle Arrest

ABSTRACT A classical cellular response to hypoxia is a cessation of growth. Hypoxia-induced growth arrest differs in different cell types but is likely an essential aspect of the response to wounding and injury. An important component of the hypoxic response is the activation of the hypoxia-inducible factor 1 (HIF-1) transcription factor. Although this transcription factor is essential for adaptation to low oxygen levels, the mechanisms through which it influences cell cycle arrest, including the degree to which it cooperates with the tumor suppressor protein p53, remain poorly understood. To determine broadly relevant aspects of HIF-1 function in primary cell growth arrest, we examined two different primary differentiated cell types which contained a deletable allele of the oxygen-sensitive component of HIF-1, the HIF-1α gene product. The two cell types were murine embryonic fibroblasts and splenic B lymphocytes; to determine how the function of HIF-1α influenced p53, we also created double-knockout (HIF-1α null, p53 null) strains and cells. In both cell types, loss of HIF-1α abolished hypoxia-induced growth arrest and did this in a p53-independent fashion. Surprisingly, in all cases, cells lacking both p53 and HIF-1α genes have completely lost the ability to alter the cell cycle in response to hypoxia. In addition, we have found that the loss of HIF-1α causes an increased progression into S phase during hypoxia, rather than a growth arrest. We show that hypoxia causes a HIF-1α-dependent increase in the expression of the cyclin-dependent kinase inhibitors p21 and p27; we also find that hypophosphorylation of retinoblastoma protein in hypoxia is HIF-1α dependent. These data demonstrate that the transcription factor HIF-1 is a major regulator of cell cycle arrest in primary cells during hypoxia.

Distinct Human Cell Populations Produce Rapidly Detectable Levels of Neutrophils and Platelets in NOD/SCID-IL-2Receptor Gamma Chain Null Mice Transgenically Engineered to Produce Human Myeloid Growth Factors

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1892-1892
Author(s):  
Paul H. Miller ◽  
Alice M.S. Cheung ◽  
Suzan Imren ◽  
Philip A Beer ◽  
Shabnam Rostamirad ◽  
...  
Keyword(s):  
Progenitor Cell ◽  
Cell Types ◽  
Human Cells ◽  
Human Neutrophils ◽  
Short Term ◽  
Steel Factor ◽  
Gm Csf ◽  
Nsg Mice ◽  
Cd34 Cells

Abstract Abstract 1892 Cord blood (CB) is becoming an increasingly utilized source of cells for cancer patients who are eligible for therapies that require a transplant to rescue them from toxic side effects on their own hematopoietic cells but lack a suitable HLA-matched donor. This strategy is now routinely used in children, but delayed neutrophil and platelet recovery remain unsolved problems and these problems are exacerbated in adults. To address this issue, we first surveyed the variability in 8 individual CB harvests of parameters routinely used to predict the utility of CB units as transplants (i.e., CD34+ and in vitro myeloid clonogenic progenitor cell frequencies). In addition, we compared their 3-week outputs of CD33/15/66+ cells (neutrophils and monocytes) in the marrow and CD41a+ platelets in the blood of sublethally irradiated NSG mice after the IV transplantation of ∼104 CD34+ cells. These latter assessments were based on ongoing experiments in our lab demonstrating that, at this transplant dose, the outputs measured are linearly related to the number of CD34+ cells injected and detect transplantable progenitor cell types that are biologically distinct from cells with longer term repopulating activity. The results showed variation between CBs in all parameters, a marked lack of correlation between %CD34+ cells or % total CFCs in initial cells and %CD41a+ cells regenerated at 3 weeks/104 CD34+ cells transplanted (R=-0.28 and 0.35, respectively), and a weak correlation between the %CD33/15/66+ cells regenerated at 3 weeks/104 CD34+ cells transplanted and %CD34+ cells or % total CFCs in the initial CB cells (R values of 0.46–0.64). However, although engraftment of primitive human cells in NSG mice appears highly efficient, terminal differentiation of the myeloid lineages in these mice is poor. One possible explanation for this deficiency in mature cell output is that several of the murine growth factors responsible for regulating the production and release of these cells into the circulation in mice are not cross-reactive on human cells. We therefore hypothesized that engineering NSG mice to produce the human counterparts might significantly improve the detection of short term repopulating human cells whose maximum clone size might be limiting in NSG mice. Three potential relevant factors are IL-3, GM-CSF and Steel factor. We therefore backcrossed a line of transgenic NS mice we had created to express human IL-3, GM-CSF and Steel factor onto the NSG strain to produce homozygous NSG mice expressing all 3 of these human factors (NSG-3GS mice). We then compared these NSG-3GS mice with NSG mice in terms of their ability to stimulate the production within 3 weeks of human neutrophil-monocytes and platelets from intravenously transplanted CD34+ cells isolated from pooled CB harvests. The results showed that the levels of neutrophils and monocytes generated in the marrow of the NSG-3GS mice were elevated to levels of >50% of the marrow in 90% of the mice, even at the lowest number of CD34+ cells transplanted. Human neutrophils and monocytes were also elevated in the blood of the NSG-3GS mice where, despite the observed “saturation” of the marrow, there was a linear dose-response in the number of human neutrophils and monocytes present in the blood with increasing CD34+ cells infused. These findings are consistent with the reported activities of these molecules in vitro and in patients suggesting their physiological relevance in this murine xenograft model. We next utilized this assay to characterize the cells responsible for the neutrophil/monocyte and platelet repopulating activities detected in NSG-3GS mice. Preliminary assessment of the CD34+CD45RA- population on the basis of CD123 (IL-3 receptor alpha chain) expression indicates that the CD123+ fraction is enriched for short term (3-week) neutrophil/monocyte repopulating activity, while the CD123- fraction is enriched for short term (3-week) platelet repopulating activity. In summary, NSG-3GS mice significantly enhance the output of human cells with short term human myeloid repopulating ability thereby enabling neutrophil/monocyte outputs as well as platelet outputs to be assessed by analysis of peripheral blood samples. We have also used this tool to obtain evidence that these two outputs are derived from distinct cell types. Direct quantification of these may add to future predictions of graft quality. Disclosures: No relevant conflicts of interest to declare.

Glioblastoma-derived cells exhibit differential responses to glycolysis inhibition under hypoxia

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e13031-e13031
Author(s):  
F. Pistollato ◽  
S. Abbadi ◽  
E. Rampazzo ◽  
G. Viola ◽  
A. Della Puppa ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Oxygen Tension ◽  
Side Population ◽  
Hypoxia Inducible Factor ◽  
Glucose Deprivation ◽  
The Elderly ◽  
Resistant Cell ◽  
Response To Therapy ◽  
Crucial Component

e13031 It has been suggested that oxygen tension is a crucial component of the brain tumor niche, as hypoxia positively correlates with tumor aggressiveness and over-activity of hypoxia inducible factor-1α (HIF-1α) reinforces tumor progression. Furthermore, hypoxia has been implicated in the regulation of several signaling pathways (Notch, BMP), angiogenesis and importantly, glucose metabolism. Here we investigate the effects mediated by in vitro glycolysis inhibition by using 2-deoxyglucose (2-DG) in glioblastoma (GBM) derived cells maintained under two different oxygen tensions, a lowered oxygen tension (2%) versus a higher non-physiological (20%). GBM account for 50% of all gliomas and arise after age 50 in most patients and it has been seen that younger patients tend to have a better prognosis than the elderly. Our results show that adult GBM displaying a highly immature phenotype manifested the highest resistance to glucose deprivation. Furthermore, increase of multi-drug resistant cell fraction, described as side population, occurred following 2-DG treatment, but only under hypoxia. Neuronal committed precursors were selected by 2-DG, but these effects were mitigated by hypoxia. Also, hypoxia inhibits the mitochondria-controlled apoptosis induced by 2-DG, by conferring cell resistance through progressive activation of pro-survival NF-kB and induction of tumor cell autophagy. Importantly, HIF-1α level reduction and proline hydroxylase 2 (PHD2) upregulation occurred following 2-DG treatment even under hypoxia, and this may depend on reactive oxygen species reduction. These results indicate differences in tumor cells behavior that may be predictive of cell response to therapy aiming to limit glucose uptake or glucose metabolism. No significant financial relationships to disclose.

scholarly journals Effect of probiotics on the viability of porcine and human neutrophils in vitro

2017 ◽  
Vol 62 (No. 12) ◽  
pp. 637-646
Author(s):  
T. Sustrova ◽  
P. Ondrackova ◽  
L. Leva ◽  
M. Kolarova ◽  
P. Kulich ◽  
...  
Keyword(s):  
Tissue Regeneration ◽  
Lactobacillus Rhamnosus ◽  
Bifidobacterium Bifidum ◽  
Human Neutrophils ◽  
Neutrophil Apoptosis ◽  
Large White ◽  
Healthy Human ◽  
Lactate Dehydrogenase Activity ◽  
Late Apoptosis

Lactobacillus, Bifidobacterium and Enterococcus cultures are increasingly used as probiotics for humans and pigs. The aim of this study was to investigate if co-cultivation of porcine and human neutrophils with probiotics can lead to increased apoptosis in vitro. Ten adult Large white pigs and 10 healthy human donors were used in this study. Neutrophils were isolated by dextran sedimentation and cultivated with and without the lactic acid bacteria Bifidobacterium bifidum, Lactobacillus rhamnosus, and Enterococcus faecium for 2, 4, 24 and 48 h. Early and late apoptosis was measured using flow cytometry, and cell lysis was detected based on lactate dehydrogenase activity (LDH). A significant (P < 0.05; P < 0.01) increase in apoptotic neutrophils and LDH was observed at 24 h and 48 h in vitro. All probiotics exerted their greatest effects on the early apoptosis of porcine neutrophils, while the effects of L. rhamnosus were most pronounced on late apoptosis and those of B. bifidum on LDH release of human neutrophils. The increased neutrophil apoptosis caused by probiotic bacteria can be beneficial for more efficient efferocytosis and faster resolution of inflammation and tissue regeneration. In conclusion, we have demonstrated that the interaction of B. bifidum, L. rhamnosus, and E. faecium with human and porcine neutrophils leads to their apoptosis.

scholarly journals HIF-stabilization prevents delayed fracture healing

2020 ◽  
Author(s):  
Annemarie Lang ◽  
Sarah Helfmeier ◽  
Jonathan Stefanowski ◽  
Aditi Kuppe ◽  
Vikram Sunkara ◽  
...  
Keyword(s):  
Fracture Healing ◽  
Hypoxia Inducible Factor ◽  
Cost Effective ◽  
Supporting Cell ◽  
Adaptation To Hypoxia ◽  
Preventive Strategy ◽  
Low Oxygen ◽  
Cellular Adaptation

AbstractThe initial phase of fracture healing decides on success of bone regeneration and is characterized by an inflammatory milieu and low oxygen tension (hypoxia). Negative interference with or prolongation of this fine-tuned initiation phase will ultimately lead to a delayed or incomplete healing such as non-unions which then requires an effective and gentle therapeutic intervention. Common reasons include a dysregulated immune response, immunosuppression or a failure in cellular adaptation to the inflammatory hypoxic milieu of the fracture gap and a reduction in vascularizing capacity by environmental noxious agents (e.g. rheumatoid arthritis, smoking). The hypoxia-inducible factor (HIF)-1α is responsible for the cellular adaptation to hypoxia, activating angiogenesis and supporting cell attraction and migration to the fracture gap. Here, we hypothesized that stabilizing HIF-1α could be a cost-effective and low-risk prevention strategy of fracture healing disorders. Therefore, we combined a well-known HIF-stabilizer – deferoxamine (DFO) – and a less known HIF-enhancer – macrophage migration inhibitory factor (MIF) – to synergistically induce improved fracture healing. Stabilization of HIF-1α enhanced calcification and osteogenic differentiation of MSCs in vitro. In vivo, the application of DFO with or without MIF during the initial healing phase accelerated callus mineralization and vessel formation in a clinically relevant mouse-osteotomy-model in a compromised healing setting. Our findings provide support for a promising preventive strategy towards bone healing disorders in patients with a higher risk due to e.g. delayed neovascularization by accelerating fracture healing using DFO and MIF to stabilize HIF-1α.

scholarly journals miR-21 increases c-kit+ cardiac stem cell proliferation in vitro through PTEN/PI3K/Akt signaling

PeerJ ◽  
2017 ◽  
Vol 5 ◽  
pp. e2859 ◽  
Author(s):  
Bei Shi ◽  
Wenwen Deng ◽  
Xianping Long ◽  
Ranzun Zhao ◽  
Yan Wang ◽  
...  
Keyword(s):  
Mrna Level ◽  
Cell Types ◽  
Ischemic Myocardium ◽  
Akt Pathway ◽  
Pi3k Inhibitor Ly294002 ◽  
Over Expression ◽  
Tensin Homolog ◽  
Survival Effect ◽  
Proliferation In Vitro

The low survival rate of cardiac stem cells (CSCs) in the ischemic myocardium is one of the obstacles in ischemic cardiomyopathy cell therapy. The MicroRNA (miR)-21 and one of its target protein, the tensin homolog deleted on chromosome ten (PTEN), contributes to the proliferation of many kinds of tissues and cell types. It is reported that miR-21 promotes proliferation through PTEN/PI3K/Akt pathway, but its effects on c-kit+ CSC remain unclear. The authors hypothesized that miR-21 promotes the proliferation in c-kit+ CSC, and evaluated the involvement of PTEN/PI3K/Akt pathway in vitro. miR-21 up-regulation with miR-21 efficiently mimics accelerated cell viability and proliferation in c-kit+ CSC, which was evidenced by the CCK-8, EdU and cell cycle analyses. In addition, the over-expression of miR-21 in c-kit+ CSCs notably down-regulated the protein expression of PTEN although the mRNA level of PTEN showed little change. Gain-of-function of miR-21 also increased the phosphor-Akt (p-Akt) level. Phen, the selective inhibitor of PTEN, reproduced the pro-proliferation effects of miR-21, while PI3K inhibitor, LY294002, totally attenuated the pro-survival effect of miR-21. These results indicate that miR-21 is efficient in promoting proliferation in c-kit+ CSCs, which is contributed by the PTEN/PI3K/Akt pathway. miR-21 holds the potential to facilitate CSC therapy in ischemic myocardium.

Implications for Preeclampsia: Hypoxia-Induced Notch Promotes Trophoblast Migration

Reproduction ◽  
2021 ◽  
Author(s):  
Barry E Perlman ◽  
Audrey A Merriam ◽  
Alexander Lemenze ◽  
Qingshi Zhao ◽  
Salma Begum ◽  
...  
Keyword(s):  
Notch Signaling ◽  
Oxygen Tension ◽  
Cell Types ◽  
Cellular Migration ◽  
Migration And Invasion ◽  
Cellular Motility ◽  
Low Oxygen ◽  
Notch Activation ◽  
Trophoblast Migration

In the 1st trimester of human pregnancy, low oxygen tension or hypoxia, is essential for proper placentation and placenta function. Low oxygen levels and activation of signaling pathways have been implicated as critical mediators in the promotion of trophoblast differentiation, migration, and invasion with inappropriate changes in oxygen tension and aberrant Notch signaling both individually reported as causative to abnormal placentation. Despite crosstalk between hypoxia and Notch signaling in multuple cell types, the relationship between hypoxia and Notch in 1st trimester trophoblast function is not understood. To determine how a low oxygen environment impacts Notch signaling and cellular motility, we utilized the human 1st trimester trophoblast cell line, HTR-8/SVneo. Gene set enrichment and ontology analyses identified pathways involved in angiogenesis, Notch and cellular migration as upregulated in HTR-8/SVneo cells exposed to hypoxic conditions. DAPT, a -secretase inhibitor that inhibits Notch activation, was used to interrogate the crosstalk between Notch and hypoxia pathways in HTR-8/SVneo cells. We found that hypoxia requires Notch activation to mediate HTR-8/SVneo cell migration, but not invasion. To determine if our in vitro findings were associated with preeclampsia, we analyzed 2nd trimester chorionic villous sampling (CVS) samples and 3rd trimester placentas. We found a significant decrease in expression of migration and invasion genes in CVS from preeclamptic pregnancies, and significantly lower levels of JAG1 in placentas from pregnancies with early-onset preeclampsia with severe features. Our data support a role for Notch in mediating hypoxia-induced trophoblast migration, which may contribute to preeclampsia development.

scholarly journals Cysteinyl Leukotriene Receptor-1 Antagonists as Modulators of Innate Immune Cell Function

2014 ◽  
Vol 2014 ◽  
pp. 1-16 ◽  
Author(s):  
A. J. Theron ◽  
H. C. Steel ◽  
G. R. Tintinger ◽  
C. M. Gravett ◽  
R. Anderson ◽  
...  
Keyword(s):  
Cell Function ◽  
Immune Cell ◽  
Cell Types ◽  
Innate Immune ◽  
Human Neutrophils ◽  
Cysteinyl Leukotriene ◽  
Anti Inflammatory ◽  
Cysteinyl Leukotriene Receptor ◽  
Underlying Mechanisms

Cysteinyl leukotrienes (cysLTs) are produced predominantly by cells of the innate immune system, especially basophils, eosinophils, mast cells, and monocytes/macrophages. Notwithstanding potent bronchoconstrictor activity, cysLTs are also proinflammatory consequent to their autocrine and paracrine interactions with G-protein-coupled receptors expressed not only on the aforementioned cell types, but also on Th2 lymphocytes, as well as structural cells, and to a lesser extent neutrophils and CD8+cells. Recognition of the involvement of cysLTs in the immunopathogenesis of various types of acute and chronic inflammatory disorders, especially bronchial asthma, prompted the development of selective cysLT receptor-1 (cysLTR1) antagonists, specifically montelukast, pranlukast, and zafirlukast. More recently these agents have also been reported to possess secondary anti-inflammatory activities, distinct from cysLTR1 antagonism, which appear to be particularly effective in targeting neutrophils and monocytes/macrophages. Underlying mechanisms include interference with cyclic nucleotide phosphodiesterases, 5′-lipoxygenase, and the proinflammatory transcription factor, nuclear factor kappa B. These and other secondary anti-inflammatory mechanisms of the commonly used cysLTR1 antagonists are the major focus of the current review, which also includes a comparison of the anti-inflammatory effects of montelukast, pranlukast, and zafirlukast on human neutrophilsin vitro, as well as an overview of both the current clinical applications of these agents and potential future applications based on preclinical and early clinical studies.

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