TLR4 upregulation underpins airway neutrophilia in smokers with chronic obstructive pulmonary disease and acute respiratory failure

Pace, Elisabetta; Giarratano, A; Ferraro, Maria; Bruno, Andreina; Siena, Liboria; Mangione, Salvatore; Johnson, Malcolm; Gjomarkaj, Mark

doi:10.1016/j.humimm.2010.09.009

Cited by 58 publications

(48 citation statements)

References 37 publications

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“…Bronchoalveolar lavage (BAL) cells obtained from patients with COPD, on the other hand, showed increased TLR4 expression, which could promote airway neutrophilic inflammation (Pace et al, 2011). In Lun et al (2009) and Pace et al (2011), patient material was used, but because of the difficulty in obtaining human material, animal disease models are more often used to analyze TLR expression profiles. Differences exist between murine and human TLRs; hence, extrapolation to human diseases of findings derived from animal studies should be done with care.…”

Section: Toll-like Receptor Expression In the Respiratory Tractmentioning

confidence: 99%

Dual Role of Toll-Like Receptors in Asthma and Chronic Obstructive Pulmonary Disease

et al. 2012

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Section: Toll-like Receptor Expression In the Respiratory Tractmentioning

confidence: 99%

Dual Role of Toll-Like Receptors in Asthma and Chronic Obstructive Pulmonary Disease

et al. 2012

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“…b-defensin 2 is a neutrophil chemo-attractant produced by lung epithelial cells that is involved in host innate immune defence [23]. There are conflicting reports of b-defensin 2 levels in the lungs of COPD patients, as increased levels have been observed in broncho-alveolar lavage from COPD patients compared with controls, but decreased levels in the induced sputum of COPD patients compared with controls [22,24]. This paper reports the effects of LPS challenges in healthy smokers as a potential model of bacterial exacerbations in COPD patients.The novelty of this study is that we measured the time course of airway and systemic inflammation and the reproducibility of the challenge.…”

Section: Introductionmentioning

confidence: 99%

Inhaled LPS challenges in smokers: a study of pulmonary and systemic effects

Aul

Armstrong

Duvoix

et al. 2012

Brit J Clinical Pharma

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Neutrophilic airway inflammation is a feature of chronic obstructive pulmonary disease (COPD). Inhaled lipopolysaccharide (LPS) challenge in healthy non‐smokers has been used to assess the anti‐inflammatory effects of novel drugs on neutrophilic airway inflammation.WHAT THIS STUDY ADDS• We performed inhaled LPS challenge in smokers to study an inflammatory response in subjects who more closely resemble COPD patients. Inhaled LPS caused reproducible pulmonary inflammation in smokers, associated with changes in systemic biomarkers. Inhaled LPS appears to be a suitable model for studying exacerbations of COPD.AIMS Lipopolysaccharide (LPS) is a TLR4 agonist which activates NFκB dependent cytokine production. We investigated LPS inhalation in healthy smokers as a model of COPD bacterial exacerbations. We studied safety, reproducibility, the translocation of the NFκB subunit p65 in sputum cells and changes in systemic biomarkers of inflammation.METHODS Twelve smokers inhaled 5 and 30 µg LPS and safety was monitored over 24 h. IL‐6, CRP, CCl‐18, SP‐D, CC‐16 and β‐defensin 2 were measured in serum samples collected at baseline, 4, 8 and 24 h. Sputum was induced at baseline, 6 and 24 h for cell counts and p65 expression. Repeated challenges were performed after a 2 week interval in 10 smokers.RESULTS LPS inhalation was well tolerated. Significant increases occurred in sputum neutrophil counts with both doses, with a maximum increase of 21.5% at 6 h after 30 µg which was reproducible, ri (intraclass correlation coefficient) = 0.88. LPS increased sputum cell nuclear p65 translocation and phospho‐p65 expression. All of the serum biomarkers increased following challenge but with different temporal patterns.DISCUSSION Inhaled LPS challenge in smokers causes pulmonary and systemic inflammation that involves NFκB activation. This appears to be a suitable model for studying bacterial exacerbations of COPD.

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“…Airway epithelial cells from patients with severe COPD showed decreased expression of TLR4, but not TLR2 (MacRedmond et al, 2007). In contrast, recently Pace et al observed increased neutrophils and decreased apoptosis of neutrophils in the bronchoalveolar lavage and increased expression of TLR4 in airway epithelium of COPD patients providing evidence that increased TLR4 may contribute to airway neutrophilia in COPD (Pace et al, 2011). Pace et al also demonstrated increased TLR4 expression and concurrent increased CXCL-8 in response to LPS challenge in cigarette smoke exposed airway epithelial cells (Pace et al, 2008), while other investigators showed decreased TLR4 expression which was associated with reduced CXCL-8 and hBD2 production (Kulkarni et al, 2010;MacRedmond et al, 2007).…”

Section: Toll-like Receptorsmentioning

confidence: 90%