Cytokine modulators as novel therapies for airway disease

Barnes, Peter J.

doi:10.1183/09031936.01.00229901

Cited by 84 publications

(59 citation statements)

References 102 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Neutrophils have also been shown to be a key effector cell of matrix breakdown in an animal model (8,9). Due to the fact that neutrophil recruitment in humans requires activation of the CXCR1 or CXCR2 receptors by CXC chemokines, these interactions have been explored as potential therapeutic targets (2,12). In mouse models of inflammation, neutrophil recruitment can be blocked by treatment with antibodies to MIP-2 and KC, CXCR2 antibodies (mice lack CXCR1), and CXCR2 antagonist peptides derived from CXCR2 ligands (14,17,21,37).…”

Section: Discussionmentioning

confidence: 99%

Role of CXCR2 in cigarette smoke-induced lung inflammation

Thatcher¹,

McHugh²,

Egan³

et al. 2005

American Journal of Physiology-Lung Cellular and Molecular Phys

149

111

View full text Add to dashboard Cite

It has been hypothesized that the destruction of lung tissue observed in smokers with chronic obstructive pulmonary disease and emphysema is mediated by neutrophils recruited to the lungs by smoke exposure. This study investigated the role of the chemokine receptor CXCR2 in mediating neutrophilic inflammation in the lungs of mice acutely exposed to cigarette smoke. Exposure to dilute mainstream cigarette smoke for 1 h, twice per day for 3 days, induced acute inflammation in the lungs of C57BL/6 mice, with increased neutrophils and the neutrophil chemotactic CXC chemokines macrophage inflammatory protein (MIP)-2 and KC. Treatment with SCH-N, an orally active small molecule inhibitor of CXCR2, reduced the influx of neutrophils into the bronchoalveolar lavage (BAL) fluid. Histological changes were seen, with drug treatment reducing perivascular inflammation and the number of tissue neutrophils. β-Glucuronidase activity was reduced in the BAL fluid of mice treated with SCH-N, indicating that the reduction in neutrophils was associated with a reduction in tissue damaging enzymes. Interestingly, whereas MIP-2 and KC were significantly elevated in the BAL fluid of smoke exposed mice, they were further elevated in mice exposed to smoke and treated with drug. The increase in MIP-2 and KC with drug treatment may be due to the decrease in lung neutrophils that either are not present to bind these chemokines or fail to provide a feedback signal to other cells producing these chemokines. Overall, these results demonstrate that inhibiting CXCR2 reduces neutrophilic inflammation and associated lung tissue damage due to acute cigarette smoke exposure.

show abstract

Section: Discussionmentioning

confidence: 99%

Role of CXCR2 in cigarette smoke-induced lung inflammation

Thatcher¹,

McHugh²,

Egan³

et al. 2005

American Journal of Physiology-Lung Cellular and Molecular Phys

149

111

View full text Add to dashboard Cite

show abstract

“…This suggests that inhibitors of TNF-␣ might be useful in reversing the skeletal wasting seen in COPD as well as reducing the airway inflammatory response (Barnes, 2001a).…”

Section: Effectsmentioning

confidence: 99%

Mediators of Chronic Obstructive Pulmonary Disease

2004

View full text Add to dashboard Cite

“…These NF-B regulated mediators (e.g., TNF␣, IL-8, IL-6, IL-1␤, MIP-1␣, and GRO␣) have been suggested to play a central role in a variety of acute and chronic inflammatory diseases (Barnes, 2001). Therefore, it has been suggested that blocking the NF-B pathway represents a possible disease-modifying therapy (Barnes and Adcock, 1997).…”

mentioning

confidence: 99%

IκB Kinase-2-Independent and -Dependent Inflammation in Airway Disease Models: Relevance of IKK-2 Inhibition to the Clinic

Birrell

Wong²,

Hardaker³

et al. 2006

Mol Pharmacol

View full text Add to dashboard Cite

Nuclear factor B (NF-B) is a transcription factor believed to be central in the expression of numerous inflammatory genes and the pathogenesis of many respiratory diseases. We have previously demonstrated increased NF-B pathway activation in a steroid-sensitive animal model of lipopolysaccharide (LPS)-driven airway inflammation. It is noteworthy that this phenomenon was not observed in a steroid-insensitive model of elastase-induced inflammation in the rat. The aim of this study was to gather further evidence to suggest that these similar profiles of neutrophilic inflammation can be NF-B-dependent or -independent by determining the impact of an IB kinase-2 (IKK-2) inhibitor, 2-[(aminocarbonyl)amino]-5-(4-fluorophenyl)-3-thiophenecarboxamide (TPCA-1). In the LPS model, TPCA-1 blocked the increase in NF-B DNA binding, a marker of NF-B pathway activation. This inhibition was associated with a reduction in inflammatory mediator release [tumor necrosis factor ␣ (TNF␣)/interleukin-1␤ (IL-1␤)/matrix metalloproteinase-9 (MMP-9)] and lung inflammatory cell burden (neutrophilia/eosinophilia). These data were paralleled with a steroid and in human cell based assays. In the elastase-driven inflammation model, in which our group has previously failed to measure an increase in NF-B DNA binding, neither TPCA-1 nor the steroid, affected mediator release (IL-1␤/MMP-9) or cellular burden (neutrophilia/lymphomononuclear cells). This is the first study to examine the effect of an IKK-2 inhibitor in well validated models that mimic aspects of the inflammatory lesion evident in diseases such as COPD. In conclusion, we have demonstrated that animal models with similar profiles of airway inflammation can be IKK-2 inhibitor/steroid-sensitive or -insensitive. If both profiles of inflammation exist in the clinic, then this finding is extremely exciting and may lead to greater understanding of disease pathology and the discovery of novel anti-inflammatory targets.

show abstract

Cytokine modulators as novel therapies for airway disease

Cited by 84 publications

References 102 publications

Role of CXCR2 in cigarette smoke-induced lung inflammation

Role of CXCR2 in cigarette smoke-induced lung inflammation

Mediators of Chronic Obstructive Pulmonary Disease

IκB Kinase-2-Independent and -Dependent Inflammation in Airway Disease Models: Relevance of IKK-2 Inhibition to the Clinic

Contact Info

Product

Resources

About