IL-8We have used induced sputum samples and counted cells expressing HO-1, iNOS, and nitroty-rosine, and levels of soluble inflammatory mediators in patients with COPD who were hospitalized for severe exacerbation compared to stable state. The results showed significantly increased MPO, IL-8, nitrotyrosine, and HO-1 expression in patients during exacerbation relative to the stable state. These findings provide further insight into the pathogenesis of COPD exacerbations.

There are several limitations regarding our study. First, we did not examine them for evidence of acute viral infection, or for infection with chlamydia or mycoplasma, which are often detected during COPD exacerbations. Second, it was difficult to accurately differentiate between chronic bacterial colonization of the respiratory tract and acute infection. We tried to overcome this difficulty by comparing sputum samples obtained from patients during exacerbations with those obtained from the same patients in the stable state. Third, due to significant comorbidities in the majority of COPD patients who were admitted for severe exacerbations, we were only able to recruit a relatively limited number of patients. However, the power of our results was tested, and it was found to be > 80%. Therefore, a type 1 statistical error is unlikely. Fourth, the present study used sputum analysis to assess airway inflammation. It is known that dithiothreitol (DTT), a reducing agent that is regularly used to homogenize sputum, may affect the detection of inflammatory mediators in the sputum sol phase. However, other investigators have shown good recovery of sputum ECP, MPO, IL-8, and GM-CSF using commercial immunoassays, as well as no effect of DTT on their standard curves. Even if DTT affects any of these measurements, comparability between samples obtained from patients during exacerbations or while in the stable state was preserved.

BiopsyPreviously published studies have associated inflammation with COPD exacerbations. Increased numbers of inflammatory cells and elevated levels of various mediators have been reported in biopsy, BAL, and induced sputum samples obtained from COPD patients during exacerbations. Differences in airway inflammation have been reported between patients with mild or severe exacerbations. Specifically, airway eosinophilia has been related to mild exacerbation, while airway neutrophilia has been related to severe exacerbation. Neutrophil che-mokines IL-8 and epithelial-derived neutrophil at-tractant-78 (CXCL5) and chemokine receptors CXCR1 and CXCR2 appear to play an important role in airway neutrophilia, which is characteristic of severe exacerbations. This web site Canadian health&care mall news website will be a good supplier of information for you. What kind of information – a medical one of course.

The present study demonstrated increased sputum neutrophil levels, and increased sputum IL-8 and MPO levels at the onset of a severe COPD exacerbation requiring hospital admission (Fig 1). MPO is a granule proteolytic protein that is released from neutrophils during their activation, and proteolysis could be a primary mechanism of neutrophil-induced injury during COPD exacerbation. IL-8 is primarily known for its chemotactic action on neutrophils. Qiu et al have reported a positive association between the numbers of neutrophils and cells with messenger RNA that is positive for IL-8 in endobronchial biopsy specimens from COPD patients during severe exacerbation. However, we failed to find any correlation between sputum IL-8 levels and sputum neutrophils. This discrepancy could be attributed to the fact that we have studied protein while Qiu et al studied messenger RNA, or that we have studied sputum samples while Qiu et al studies endobronchial biopsy specimens. Moreover, the recruitment of neutrophils in the airways of COPD patients is induced by a combination of neutrophil chemokines, which often makes it difficult to correlate a specific chemokine (eg, IL-8) with neutrophil numbers. Increased levels of leukotriene B4 have also been found during COPD exacerbations, and it may be a more powerful neutrophil chemoattractant than IL-8.

Sputum neutrophiliaSputum neutrophilia and increased MPO and IL-8 levels were observed independently of the presence of bacterial infection during exacerbation. Similarly, Aaron et al found no relationship between airway inflammation and acute respiratory tract infection during exacerbation. Such results are not entirely unexpected. Factors other than infections (eg, oxidative stress) may also induce airway neutrophilia during COPD exacerbations. Oxidative stress induces the transcription of genes of various inflammatory mediators, including the IL-8 gene.

In the study by Aaron et al, only 1 of 14 COPD patients had bacterial positive exacerbation. In this study, 5 of 12 patients had bacterial positive exacerbation. The increased number of patients with bacterial airway infection may be due to the fact that we have studied patients with severe COPD who were hospitalized for severe exacerbation.

It should be noted that, unlike the dramatic increases in sputum neutrophils, IL-8, and MPO levels during exacerbation, a similar increase in eosinophils, ECP, or GM-CSF level was not observed. Considering that ECP is a cytotoxic protein that is released from eosinophils on activation and that GM-CSF is a cytokine with multiple functions, among which are the recruitment, survival, and degranulation of eosinophils, the involvement of eosinophils in severe COPD exacerbations seems to be unlikely, which further supports the hypothesis of a different inflammatory profile for exacerbations of different severity, such as neutrophilia during severe exacerbations and eosinophilia during mild exacer-bations.

iNOSFor the purposes of the present study, we also measured immunoreactivity for iNOS and nitroty-rosine. iNOS expression is induced under inflammatory and oxidant conditions, and nitrotyrosine formation is increased in the presence of reactive oxygen species, as in the airways of stable COPD patients.- Although previous investigators have suggested’ that oxidative stress is further increased during COPD exacerbations, we did not find a significant increase in total sputum iNOS +ve inflammatory cells (percentages and absolute counts) during severe COPD exacerbations. An explanation of this discrepancy could be that inhaled steroid treatment suppressed increased iNOS expression. It may be that further studies, including those with steroid-naive patients, are needed to identify the changes in iNOS expression during COPD exacerbations. On the other hand, we found significantly increased percentages and absolute numbers of ni-trotyrosine +ve sputum inflammatory cells. These observations indicate that NO consumption through oxidant mechanisms is increased during a severe COPD exacerbation. NO elicits a diverse array of physiologic and pathophysiologic effects. Nitrosa-tive stress and nitration of proteins may inhibit physiologic protein function and induce oxidative DNA damage during COPD exacerbations. There might be a clinical benefit from inhibiting iNOS expression and nitrotyrosine formation during exacerbation, which supports the potential role of NO modulators in the treatment of exacerbations. Preliminary results have suggested that NO synthase inhibitors and NO donors that are administered regularly may have clinical benefits for COPD patients, but there are no data regarding COPD exacerbations.

Severe COPDUnder physiologic conditions, inflammation and oxidative stress induce HO-1, which protects against inflammatory and oxidant-mediated cellular injury. The mechanisms by which HO-1 mediates these cytoprotective functions are not clear. However, the three major catalytic byproducts, carbon monoxide, ferritin, and bilirubin represent potential targets. Increased HO-1 expression has been reported in smokers, and decreased HO-1 expression has been reported in patients with severe COPD. Having demonstrated increased airway inflammation and nitrosative stress in COPD patients during severe exacerbations, we expected and found an increase in HO-1 expression (Fig 2). However, it is possible that this increase was not sufficient to protect the patient from lung injury. This is an intriguing hypothesis, which further highlights the possibility for a different therapeutic approach to COPD exacerbations in the future. For example, the exogenous administration of HO-1 via transgene delivery in rats provides cyto-protection against hyperoxia.

In conclusion, the present study of sputum samples that were obtained at the onset of a severe COPD exacerbation demonstrated increased airway inflammation and nitrosative stress during exacerbation, accompanied by an increase in HO-1 expression. These observations may improve our understanding of the pathogenetic pathways of severe COPD exacerbations and might help in the discovery of novel therapeutic modalities to treat COPD exacerbations. However, further studies are needed to verify this hypothesis.