Evidence for Excessive Bronchial Inflammation during an Acute Exacerbation of Chronic Obstructive Pulmonary Disease in Patients with α₁-Antitrypsin Deficiency (PiZ)

Abstract

Patients with homozygous (PiZ) alpha(1)-antitrypsin (AAT) deficiency have not only low baseline serum AAT levels (approximately 10 to 15% normal) but also an attenuated acute phase response. They are susceptible to the development of premature emphysema but may also be particularly susceptible to lung damage during bacterial exacerbations when there will be a significant neutrophil influx. The purposes of the present study were to assess the inflammatory nature of acute bacterial exacerbations of chronic obstructive pulmonary disease (COPD) in subjects with AAT deficiency, to compare this with COPD patients without deficiency, and to monitor the inflammatory process and its resolution following appropriate antibacterial therapy. At the start of the exacerbation, patients with AAT deficiency had lower sputum AAT (p < 0.001) and secretory leukoprotease inhibitor (SLPI; p = 0.02) with higher elastase activity (p = 0.02) compared with COPD patients without deficiency. Both groups had a comparable acute phase response as assessed by C-reactive protein (CRP) but the AAT-deficient patients had a minimal rise in serum AAT (to < 6 microM). After treatment with antibiotics, in patients with AAT deficiency, there were significant changes in many sputum proteins including a rise in SLPI levels, and a reduction in myeloperoxidase (MPO) and elastase activity (p < 0. 005 for all measures); the sputum chemoattractants interleukin-8 (IL-8) and leukotriene B(4) (LTB(4)) fell (p < 0.01), and protein leak (sputum/serum albumin ratio) became lower (p < 0.01). The changes were rapid and within 3 d of the commencement of antibiotic therapy the biochemical markers had decreased significantly, but took a variable time thereafter to return to baseline values. In conclusion, patients with AAT deficiency had evidence of increased elastase activity at the start of the exacerbation when compared with nondeficient COPD patients which probably reflects a deficient antiproteinase screen (lower sputum AAT and SLPI). The increased bronchial inflammation at presentation resolved rapidly with 14 d of antibiotic therapy.

Small airway-on-a-chip enables analysis of human lung inflammation and drug responses in vitro

“…In other words, the healthy epithelium is indeed more tolerant to these pathogenic stimuli, which is consistent with the emerging concept in immunology of tolerance or resilience 6 . It is also in line with previous observation that COPD patients exhibit exaggerated inflammation and immune responses 7 . Thus, it is likely that a higher dose of LPS or poly I:C is required to elicit similar pro-inflammatory profile in healthy cells.…”

“…However, lung inflammation is mediated by organ-level responses that involve complex tissuetissue interactions between the lung airway epithelium and underlying microvascular endothelium that modulate immune reactions to respiratory pathogens and allergens [13][14][15] and alter the vascular cell adhesion molecular machinery that recruits circulating immune cells, such as neutrophils. This is important because neutrophil accumulation in the lung is associated with enhanced severity of airflow limitation in COPD patients 7 and it plays a critical role in severe asthma as well 8 . Unfortunately, it is not possible to study complex interactions among airway epithelium, endothelium and circulating neutrophils using existing in vitro lung models because most fail to recapitulate normal functional coupling between the epithelium and endothelium, and none enable analysis of recruitment of circulating immune cells under active fluid flow.…”

Acute-Phase Protein α1-Antitrypsin Inhibits Neutrophil Calpain I and Induces Random Migration

“…AAT has also been shown to reduce neutrophil infiltration into kidneys during ischemia/reperfusion (10). Until recently, the most beneficial effects of AAT were attributed to its inhibition of neutrophil elastase activity (16). However, novel studies show that AAT directly inhibits the activity of caspase-3, an intracellular cysteine protease that plays an essential role in cell apoptosis (17,18), and the catalytic domain of matriptase (19), a cell surface serine protease involved in the activation of epithelial sodium channels.…”

Markers of emphysema are associated with more severe chronic obstructive pulmonary disease

“…In fact, excess free elastase activity can be detected at high levels in lung secretions particularly during acute bacterial exacerbations. [36] Desmosine, an elastin-derived, cross-linked amino acid, has been shown to be elevated in the urine of patients with COPD. [37][38] Our study confirms and extends these results, demonstrating an increase of desmosines also in induced sputum, a more immediate site of the disease, following the preliminary results obtained in spontaneous sputum by HPLC-mass spectrometry.…”