Airways inflammation in chronic bronchitis: the effects of smoking and alpha1-antitrypsin deficiency

Abstract

Airways inflammation in chronic bronchitis is thought predominantly to be a direct consequence of neutrophil recruitment and release of elastase in response to factors such as cigarette smoke. The aims of this study were to assess the role of smoking and determine whether the serum elastase inhibitor α1‐antitrypsin (α1AT) influenced the process. Airways inflammation was compared between patients with chronic obstructive bronchitis with (n=39) and without (n=42) severe α1AT deficiency. The authors assessed the sputum concentration of the neutrophil chemoattractants interleukin‐8 (IL‐8) and leukotriene (LT)B4, myeloperoxidase (MPO) as a marker of neutrophil influx, neutrophil elastase activity and its natural inhibitors, α1AT and secretory leukoprotease inhibitor (SLPI). Finally serum α1AT was measured to determine the degree of protein leakage (sputum sol serum α1AT ratio). Compared to current smokers, the exsmokers had a lower concentration of the chemoattractant IL‐8 (p<0.05) and a lower MPO concentration, although this failed to reach conventional statistical significance (p=0.06). Patients with α1AT deficiency had greater inflammation in the larger airways with increased LTB4 (p<0.005), MPO (p<0.001), neutrophil elastase activity (p<0.01), protein leak (p<0.001), and were found to have a lower anti‐proteinase screen with both reduced sputum α1AT (p<0.001) and SLPI concentrations (p<0.05). The reduction in sputum interleukin‐8 levels in exsmokers may decrease neutrophil influx and thus explain the slower rate of neutrophil mediated progression of lung disease compared to subjects who continue to smoke. Patients with α1‐antitrypsin deficiency had greater inflammation suggesting that α1‐antitrypsin plays an important role in protecting the larger airways from the inflammatory effects of elastase activity and may explain their more rapid progression of disease.

Persistent Airway Inflammation and Emphysema Progression on CT Scan in Ex-Smokers Observed for 4 Years

“…resected lungs, 8,9 bronchial biopsies, [10][11][12] or induced sputum. [13][14][15] For example, there was no difference in the intensity of infl ammation in central and peripheral airways in studies of the resected lungs of smokers and ex-smokers undergoing surgery for a lung tumor. 8,9 Studies of bronchial biopsy specimens of smokers and ex-smokers with moderate to severe COPD have also demonstrated no difference in mediators of infl ammation associated with neutrophil and mononuclear cell recruitment, such as IL-8 and monocyte chemoattractant protein (MCP)-1, as well as the MCP-1 chemokine receptor 2, in the lung tissue.…”

“…10 Although cross-sectional studies of lung tissue in COPD demonstrate more consistent fi ndings of persistent infl ammation in ex-smokers, 3,[8][9][10][11] cross-sectional studies of sputum, blood, or BAL generally demonstrate reductions in biomarkers of infl ammation 3 or no difference in ex-smokers vs smokers. 3,[13][14][15] In the only longitudinal study of the effect of smoking cessation on airway infl ammation in COPD, 12 subjects with COPD (defi ned by pulmonary function and not by CT scan) were found to have persistent airway infl ammation in bronchial biopsy specimens and a signifi cant increase in the number of sputum neutrophils and IL-8 levels at 1 year. 6 Although these studies 3,[8][9][10][11][12][13][14][15] have provided important information regarding the potential for continued airway infl ammation following smoking cessation in COPD, the studies have mainly been cross-sectional and have focused on subjects with chronic bronchitis rather than subjects with chest CT scan-diagnosed COPD-emphysema (COPD-E).…”

“…3,[13][14][15] In the only longitudinal study of the effect of smoking cessation on airway infl ammation in COPD, 12 subjects with COPD (defi ned by pulmonary function and not by CT scan) were found to have persistent airway infl ammation in bronchial biopsy specimens and a signifi cant increase in the number of sputum neutrophils and IL-8 levels at 1 year. 6 Although these studies 3,[8][9][10][11][12][13][14][15] have provided important information regarding the potential for continued airway infl ammation following smoking cessation in COPD, the studies have mainly been cross-sectional and have focused on subjects with chronic bronchitis rather than subjects with chest CT scan-diagnosed COPD-emphysema (COPD-E). In addition, most studies have not used CT scan to defi ne subjects as having emphysema as an entry criterion and have not used blood cotinine levels to verify smoking status.…”

Liver Disease in Alpha-1 Antitrypsin Deficiency

“…However, if its activity is uncontrolled, it can injure a variety of structural components of normal tissues, and uncontrolled leukocyte elastase may also be pro-inflammatory. [7][8][9] Deficiency of AAT removes a major control mechanism for leukocyte elastase, and this deficiency can allow leukocyte elastase to injure the delicate gas-exchanging region of the lung, eventually leading to pulmonary emphysema.…”

Airway inflammation in COPD: physiological outcome measures and induced sputum

“…The characteristic sputum changes in smokers or nonsmokers with COPD are neutrophilia [43,62,94,[99][100][101], increased neutrophil proteases (myeloperoxidase (MPO) [43,73,98,[102][103][104], elastase [73,98,[102][103][104] and human neutrophil lipokalin [43]), increased chemokines (interleukin (IL)-8 [73,98,[102][103][104][105][106], IL-6 [98,107], tissue necrosis factor (TNF)-a [98,106] and leukotriene (LT)B 4 [98,103,104,108]) and increased markers of remodelling (matrix metalloproteinase-1 [109] and -9 [110], and a decrease in secretory leukocyte protease inhibitor (SLPI) [98,104,109] and tissue inhibitor of metalloproteinase-1 (109,110]). Sputum processed with ditheothreitol significantly reduces the detectable concentration of TNF-a, LTB 4 and MPO; IL-1b, IL-6, IL-8, SLPI and neutrophil elastase are unaffected [98].…”