Neutrophil Degranulation and the Effects of Phosphodiesterase Inhibition

Deree, Jessica; Lall, Rohan; Melbostad, Heidi; Grant, Michael D.; Hoyt, David B.; Coimbra, Raúl

doi:10.1016/j.jss.2006.02.031

Cited by 23 publications

(15 citation statements)

References 28 publications

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“…We observed a marked reduction in both MMP-2 and MMP-9 activity in those animals resuscitated with PTX ϩ RL when compared with standard RL infusion. This finding is supported by previous work from our laboratory demonstrating the beneficial effects of PTX on neutrophil degranulation in vitro and MMP activity in an animal model of sepsis [20,30]. In addition to the release of MMPs, neutrophils are capable of releasing large quantities of reactive oxygen species such as superoxide anions and hydrogen peroxide in a process known as the respiratory burst [31].…”

Section: Discussionsupporting

confidence: 78%

Pentoxifylline Attenuates Lung Injury and Modulates Transcription Factor Activity in Hemorrhagic Shock

Deree

Martins

Campos

et al. 2007

Journal of Surgical Research

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Section: Discussionsupporting

confidence: 78%

Pentoxifylline Attenuates Lung Injury and Modulates Transcription Factor Activity in Hemorrhagic Shock

Deree

Martins

Campos

et al. 2007

Journal of Surgical Research

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“…Tumor necrosis factor receptor superfamily, member 5 (TNFRSF5) is a key signaling molecule expressed by antigenpresenting cells of the immune system. Our detected TNFRSF5 up-regulations in SARS-CoV infection, may activate T cells and induce adhesion molecules such as carcino embryonic antigen related cell adhesion molecule 8 (CEACAM8), which is expressed by activated monocytes and granulocytes to overcome the invading microorganisms (Deree et al, 2006), also up-regulated in our study.…”

Section: Characterization Of Gene Expression Profiles Of Sars-cov Infsupporting

confidence: 60%

Elucidating the molecular physiopathology of acute respiratory distress syndrome in severe acute respiratory syndrome patients

et al. 2009

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Acute respiratory distress syndrome (ARDS) is a severe form of acute lung injury. It is a response to various diseases of variable etiology, including SARS-CoV infection. To date, a comprehensive study of the genomic physiopathology of ARDS (and SARS) is lacking, primarily due to the difficulty of finding suitable materials to study the disease process at a tissue level (instead of blood, sputa or swaps). Hereby we attempt to provide such study by analyzing autopsy lung samples from patient who died of SARS and showed different degrees of severity of the pulmonary involvement. We performed real-time quantitative PCR analysis of 107 genes with functional roles in inflammation, coagulation, fibrosis and apoptosis; some key genes were confirmed at a protein expression level by immunohistochemistry and correlated to the degree of morphological severity present in the individual samples analyzed. Significant expression levels were identified for ANPEP (a receptor for CoV), as well as inhibition of the STAT1 pathway, IFNs production and CXCL10 (a T-cell recruiter). Other genes unassociated to date with ARDS/SARS include C1Qb, C5R1, CASP3, CASP9, CD14, CD68, FGF7, HLA-DRA, IGF1, IRF3, MALAT-1, MSR1, NFIL3, SLPI, USP33, CLC, GBP1 and TAC1. As a result, we proposed to therapeutically target some of these genes with compounds such as ANPEP inhibitors, SLPI and dexamethasone. Ultimately, this study may serve as a model for future, tissue-based analyses of fibroinflammatory conditions affecting the lung.

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“…However, neutrophils recruited to the site of infection are assumed to play a major role in combating A. fumigatus infections (39). Neutrophils produce strong oxidative bursts and release proteolytic enzymes during degranulation (17). These activities not only contribute to killing of pathogens but also may cause severe tissue damage.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of Lysine Biosynthesis as an Antifungal Drug Target: Biochemical Characterization of Aspergillus fumigatus Homocitrate Synthase and Virulence Studies

2010

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Aspergillus fumigatus is the main cause of severe invasive aspergillosis. To combat this life-threatening infection, only limited numbers of antifungals are available. The fungal ␣-aminoadipate pathway, which is essential for lysine biosynthesis, has been suggested as a potential antifungal drug target. Here we reanalyzed the role of this pathway for establishment of invasive aspergillosis in murine models. We selected the first pathway-specific enzyme, homocitrate synthase (HcsA), for biochemical characterization and for study of its role in virulence. A. fumigatus HcsA was specific for the substrates acetyl-coenzyme A (acetyl-CoA) and ␣-ketoglutarate, and its activity was independent of any metal ions. In contrast to the case for other homocitrate synthases, enzymatic activity was hardly affected by lysine and gene expression increased under conditions of lysine supplementation. An hcsA deletion mutant was lysine auxotrophic and unable to germinate on unhydrolyzed proteins given as a sole nutrient source. However, the addition of partially purified A. fumigatus proteases restored growth, confirming the importance of free lysine to complement auxotrophy. In contrast to lysine-auxotrophic mutants from other fungal species, the mutant grew on blood and serum, indicating the existence of high-affinity lysine uptake systems. In agreement, although the virulence of the mutant was strongly attenuated in murine models of bronchopulmonary aspergillosis, virulence was partially restored by lysine supplementation via the drinking water. Additionally, in contrast to the case for attenuated pulmonary infections, the mutant retained full virulence when injected intravenously. Therefore, we concluded that inhibition of fungal lysine biosynthesis, at least for disseminating invasive aspergillosis, does not appear to provide a suitable target for new antifungals.

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Neutrophil Degranulation and the Effects of Phosphodiesterase Inhibition

Cited by 23 publications

References 28 publications

Pentoxifylline Attenuates Lung Injury and Modulates Transcription Factor Activity in Hemorrhagic Shock

Pentoxifylline Attenuates Lung Injury and Modulates Transcription Factor Activity in Hemorrhagic Shock

Elucidating the molecular physiopathology of acute respiratory distress syndrome in severe acute respiratory syndrome patients

Evaluation of Lysine Biosynthesis as an Antifungal Drug Target: Biochemical Characterization of Aspergillus fumigatus Homocitrate Synthase and Virulence Studies

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