GRO alpha and interleukin-8 in Pneumocystis carinii or bacterial pneumonia and adult respiratory distress syndrome.

Previously, we elucidated the intracellular mechanisms by which neutrophil elastase (NE) up-regulates inflammatory gene expression in bronchial epithelial cells. In this study, we examine the effects of both IL-1 and NE on inflammatory gene expression in 16HBE14o− bronchial epithelial cells and investigate approaches to abrogate these inflammatory responses. IL-1 induced IL-8 protein production in time- and dose-dependent fashions, an important observation given that IL-8 is a potent neutrophil chemoattractant and a key inflammatory mediator. IL-1 and NE were shown to activate the p38 MAPK pathway in 16HBE14o− cells. Western blot analysis demonstrated IL-1R-associated kinase 1 (IRAK-1) degradation in response to stimulation with both IL-1 and NE. In addition, the expression of dominant negative IRAK-1 (IRAK-1Δ), IRAK-2Δ, or IRAK-4Δ inhibited IL-1- and NE-induced NF-κB-linked reporter gene expression. Dominant negative versions of the intracellular adaptor proteins MyD88 (MyD88Δ) and MyD88 adaptor-like (Mal P/H) abrogated NE-induced NF-κB reporter gene expression. In contrast, only MyD88Δ was found to inhibit IL-1-induced NF-κB reporter activity. We also investigated the vaccinia virus proteins, A46R and A52R, which have been shown to antagonize IL-1 signaling. Transfection with A46R or A52R cDNA inhibited IL-1- and NE-induced NF-κB and IL-8R gene expression and IL-8 protein production in primary and transformed bronchial epithelial cells. Furthermore, cytokine array studies demonstrated that IL-1 and NE can up-regulate the expression of IL-6, oncostatin M, epithelial cell-derived neutrophil activating peptide-78, growth-related oncogene family members, vascular endothelial growth factor, and GM-CSF, with induction of these proteins inhibited by the viral proteins. These findings identify vaccinia virus proteins as possible therapeutic agents for the manifestations of several inflammatory lung diseases.

Section: Discussionmentioning

confidence: 96%

Viral Inhibition of IL-1- and Neutrophil Elastase-Induced Inflammatory Responses in Bronchial Epithelial Cells

Carroll

Greene

Taggart

et al. 2005

“…SARS sequelae such as transendothelial migration of polymorphonuclear cells into the lung tissues, multiple organ dysfunction, and acute respiratory distress syndrome have been postulated to associate with cytokine and chemokine dysregulation (29). IL-8 has been shown to be elevated in blood and alveolar spaces (30), and exhibits a positive correlation with the number of polymorphonuclear cells in bronchoalveolar fluid of patients with pneumonia and acute respiratory distress syndrome (31). The elevations of IL-8 and cytokines have been found in the plasma of SARS-CoV-infected patients (14) and can induce the hyperinnate inflammatory response due to the SARS-CoV invasion of the respiratory tract.…”

Section: Discussionmentioning

confidence: 99%

Induction of IL-8 Release in Lung Cells via Activator Protein-1 by Recombinant Baculovirus Displaying Severe Acute Respiratory Syndrome-Coronavirus Spike Proteins: Identification of Two Functional Regions

Chang

Liu

Chiang

et al. 2004

118

115

The inflammatory response and the intracellular signaling pathway induced by severe acute respiratory syndrome (SARS)-coronavirus (CoV) were studied in lung epithelial cells and fibroblasts. SARS-CoV spike (S) protein-encoding plasmid induced activations of IL-8 promoter and AP-1, but not NF-κB in these cells. Mutation of the AP-1, not the κB site, abolished the SARS-CoV S protein-induced IL-8 promoter activity. IL-8 release was effectively induced by vAtEpGS688, a baculovirus exhibiting the aa 17–688 fragment of S protein, and this induction was attenuated by the angiotensin-converting enzyme 2 Ab. Recombinant baculovirus expressing different deletion and insertion fragments identified the functional region of S protein from aa 324–688 (particularly the N-terminal aa 324–488 and the C-terminal aa 609–688), which is responsible for IL-8 production. Activations of AP-1 DNA-protein binding and MAPKs after vAtEpGS688 transduction were demonstrated, and SARS-CoV S protein-induced IL-8 promoter activity was inhibited by the specific inhibitors of MAPK cascades. These results suggested that the S protein of SARS-CoV could induce release of IL-8 in the lung cells via activations of MAPKs and AP-1. The identification of the functional domain for IL-8 release will provide for the drug design on targeting specific sequence domains of S protein responsible for initiating the inflammatory response.

“…Clinically, BAL levels of the CXCR ligands IL-8 and KC correlate with the severity of pulmonary neutrophilia in ARDS and pneumonia (47). In this regard, we show that KC is highly expressed in heterologously infected mice, as is another CXCR2 ligand, granulocyte chemotactic protein-2.…”

Section: Discussionmentioning

confidence: 57%

“…VILI is an aseptic cause of acute respiratory distress syndrome (ARDS), a disease that kills 26-44% of those it afflicts (45,46). VILI-minimizing strategies reduce mortality in ARDS by minimizing CXCR2 signaling, reducing neutrophil recruitment and neutrophillic injury (44,47). In contrast, in cases of ARDS resulting from infectious causes such as heterologous pneumonia, the merits of preventing immunopathology must be weighed against the potentially deleterious effects of dampening the antiviral and antibacterial host defense responses.…”

Section: Discussionmentioning

confidence: 99%

Dysregulated Macrophage-Inflammatory Protein-2 Expression Drives Illness in Bacterial Superinfection of Influenza

Zavitz¹,

Bauer²,

Gaschler³

et al. 2010

Influenza virus infection is a leading cause of death and disability throughout the world. Influenza-infected hosts are vulnerable to secondary bacterial infection, however, and an ensuing bacterial pneumonia is actually the predominant cause of influenza-attributed deaths during pandemics. A number of mechanisms have been proposed by which influenza may predispose to superinfection with an unrelated or heterologous pathogen, but the subsequent interaction between the host, virus, and bacteria remains an understudied area. In this study, we develop and examine a novel model of heterologous pulmonary infection in which an otherwise subclinical Bordetella parapertussis infection synergizes with an influenza virus infection to yield a life-threatening secondary pneumonia. Despite a profound pulmonary inflammatory response and unaltered viral clearance, bacterial clearance was significantly impaired in heterologously infected mice. No deficits were observed in pulmonary or systemic adaptive immune responses or the viability or function of infiltrating inflammatory cells to explain this phenomenon, and we provide evidence that the onset of severe pulmonary inflammation actually precedes the increased bacterial burden, suggesting that exacerbated inflammation is independent of bacterial burden. To that end, neutralization of the ELR+ inflammatory chemokine MIP-2 (CXCL2/GRO-β) attenuated the inflammation, weight loss, and clinical presentation of heterologously infected mice without impacting bacterial burden. These data suggest that pulmonary inflammation, rather than pathogen burden, is the key threat during bacterial superinfection of influenza and that selective chemokine antagonists may be a novel therapeutic intervention in cases of bacterial superinfection of influenza.