ATS 2010: Pathophysiology of COPD in AATD

    Emily F.A. van ‘t Wout | Dept. of Pulmonology, Leiden University Medical Centre, Leiden | 16 juli 2012 |

Contents:
Introduction
Role of cigarette smoke
Role of proteases
Role of respiratory infections

Introduction

Chronic obstructive pulmonary disease (COPD) is one of the most important causes of morbidity and mortality worldwide. Macrophages, which play an important role in innate and acquired immunity, are thought to contribute to the pathophysiology of the airflow obstruction and signs and symptoms of COPD. Previous studies have shown that macrophages constitute a heterogeneous population with subpopulations displaying pro-inflammatory properties (M1) and repair-inducing, anti-inflammatory properties (M2).

Alpha-1 antitrypsin (AAT) is an important neutrophil elastase inhibitor that protects lung tissue against the destructive effects of neutrophil elastase released by degranulating neutrophils. AAT deficiency (AATD) is associated with early onset COPD, with the Z-mutation (Z-AAT) covering 95% of all AAT deficient individuals. In addition, smoking is the main environmental risk factor for the development of COPD in AATD. Ahmed et al.1 showed in a meta-analysis that ZZ homozygotes have a 9.9-fold higher risk for developing COPD compared to MM individuals.
Although the hepatocyte is considered as the primary source of AAT, local production by (alveolar) macrophages and epithelial cells may contribute to the formation of an anti-elastase screen. Initially, the protease-antiprotease imbalance was thought to be the main explanation for the development of emphysema in AAT deficiency (AATD). More recently, local mechanisms operative in epithelial cells and macrophages has been implicated, including the so-called endoplasmatic reticulum (ER-) stress response due to polymerization and accumulation of the Z-AAT. This response causes cellular dysfunction, inflammation and cell death and can thereby contribute to the inflammatory environment in the lung. Besides, others have hypothesize that environmental factors can enhance the ER-stress response.

Role of cigarette smoke

For several years is known that cigarette smoke (CS) is the main risk factor for both non-AATD-COPD as AATD-COPD. Therefore, many studies have been done to the effects of CS on various cell types and factors involving COPD, such as AAT, neutrophil elastase (NE) and cytokine production.
Grandolfo2 reported that stimulation with LPS induced significant increases in interleukin (IL)-8 and IL-6 production in both alveolar epithelial cells as well as alveolar macrophages. Co-culture of those cell types synergistically increases this release. CS extract (CSE) had no effect on the LPS-induced cytokine release. In addition, Herr3 (Marburg, Germany) showed that CS suppresses the innate immune system in primary epithelial cells in response to bacterial infection by inhibiting the activation and translocation of NF-B.
The same group from Marburg4 demonstrated that smokers had significantly elevated AAT-levels in exhaled breath condensate (EBC) compared to healthy controls. However, CS is known to reduce the ability of AAT to inhibit neutrophil elastase and moreover, CS converts AAT into a pro-inflammatory stimulus5. In the emphysematous lungs of AATD patients, polymeric Z-AAT is present, which can not inhibit NE and is even chemotactic to neutrophils. The Malmö-group6 showed that CS exposure directly promotes polymerization of Z-AAT via oxidation. The polymerization of Z-AAT further reduces the anti-protease protection and attracts neutrophils, thereby increasing the lung damage.
These results implicated that CS may increase inflammation and reduce host defense, in part by enhancing the ER-stress response in epithelial cells of patients with Z-AATD.
Proteases versus antiproteases
Neutrophil elastase (NE), a neutrophil serine protease (NSP), is an enzyme which is implicated in the signs, symptoms and disease progression in COPD via its role in matrix degradation, the inflammatory process and mucus hypersecretion. The London research group7 confirmed that NE is positively correlated with tumor necrosis factor alpha (TNF), interleukin (IL)-8 and IL-1levels. Moreover, they showed that NE is related to the severity of emphysema. However, the contribution of other NSPs in CS-induced emphysema remains unknown. Guyot et al.(Reims, France)8 showed, for the first time in vivo, that all three NSPs, namely NE, cathepsin G (CG) and proteinase 3 (PR3), are involved in inflammatory changes associated with CS-induced emphysema. However, Costa9 et al. (Pisa, Italy) did not find a significant relation between severity of COPD and NE, IL-8 and inflammatory cell counts in sputum. Only the percentage blood neutrophils was significantly higher in patients with more severe COPD.
Several groups investigated the effect of AZD9668, an oral neutrophil elastase inhibitor, as a therapy for emphysema. Sanfridson et al.10 showed the selectivity of AZD9668 for NE in vitro. Stockey et al.11 showed that AZD9668 was well tolerated in patients with idiopathic bronchiectasis, as an exaggerated model of COPD inflammation, and although there was no significant difference in the primary endpoint, namely sputum neutrophil counts, signals for clinical efficacy were seen.

Role of respiratory infections

Rhinovirus (RV) infections are a major cause of exacerbations in asthma and COPD and the exacerbations are the major cause of COPD related morbidity and mortality. RV infection is thought to be one of the in vivo relevant secondary stimuli for enhancing the ER-stress response in AATD-COPD patients.
The research group of Johnston12 (London, United Kingdom) clarified that airway inflammation was greater in COPD subjects with significantly higher sputum neutrophils and NE that correlated with the severity of clinical outcomes compared to controls. The same author presented an enhanced replication rate of RV and a lowered interferon (IFN)- response on RV infection in asthma and COPD. This increased replication rate correlated with a longer duration of lower respiratory symptoms in COPD patients. Vareille et al.13 showed the same decrease in IFN production in epithelial cells from patients with cystic fibrosis (CF). This impaired IFN production resulted in increased viral replication, suggesting that in inflammatory lung diseases similar mechanisms lead to disturbances in innate immune responses to viral infection. Furthermore, one group from Australia14 showed an enhanced IL-8 and IL-6 release in CF epithelial cells infected with RV, while non-viral stimulation showed comparable levels in both CF and non-CF epithelial cells. Moreover, ER stress in CF, due to accumulation of misfolded CF-transmembrane conductance regulator (CFTR) in the endoplasmic reticulum, has been recently linked to the inflammatory response. This raises the possibility that ER stress in AATD is re;ated to impaired host defense against RV infection.
Besides viral infections, bacterial colonization is observed in a third of patients with stable COPD. Cosio16 demonstrated that exacerbations of COPD are mostly caused by Haemophilus influenzae (52%) as detected by PCR of sputum supernatants. Sputum culture was positive in 23% and the most frequently isolated bacteria were identified as P. aeruginosa and H. influenzae. Although H. influenzae is the most common pathogen, the immune response associated with this colonization is poorly understood. Millares et al.16 demonstrated that colonization by H. influenzae in patients with stable COPD is associated with a decreased local immune response (IgA) against this microorganism.

References

1. D. Ahmed, et al., Chronic obstructive pulmonary disease in α1-antitrypsin ZZ homozygotes: A meta-analysis, ERS 2010
2. D. Grandolfo, et al., Effect of toll-like receptor (TLR) agonists and cigarette smoke on primary human alveolar epithelial cells and alveolar macrophages in mono-culture and co-culture, ERS 2010
3. C. Herr, et al., Inhibition of innate host defense in airway epithelial cells by cigarette smoke in an in vitro infection model caused by suppression of NF-κB activation, LSC-ERS 2010
4. S. Noeske, et al., Smokers have elevated alpha-1-antitrypsin-values in exhaled breath condensate compared to healthy controls, ERS 2010
5. Z. Li, et al., Oxidized {alpha}1-antitrypsin stimulates the release of monocyte chemotactic protein-1 from lung epithelial cells: potential role in emphysema, Am J Physiol Lung Cell Mol Physiol., Aug;297(2):L388-400 (2009)
6. S. Alam, et al., Cigarette smoke induces polymers of Z 1-antitrypsin, ERS 2010
7. N. Snell, et al., Efficacy and safety of AZD9668, an oral neutrophil elastase inhibitor, in idiopathic bronchiectasis, ERS 2010
8. N. Guyot, et al., Deficiency in neutrophil serine proteases protects mice from the development of cigarette smoke-induced emphysema, ERS 2010
9. F. Costa, et al., Biomarkers in COPD patients: Relationship with severity indices, ERS 2010
10. A. Sanfridson, et al., AZD9668: Pharmacological characterisation of a novel oral inhibitor of neutrophil elastase (NE), ERS 2010
11. R. Stockley, et al., Efficacy and safety of AZD9668, an oral neutrophil elastase inhibitor, in idiopathic bronchiectasis, ERS 2010
12. Patrick Mallia, et al., Sputum neutrophil elastase in virus-induced COPD exacerbations correlate with clinical outcomes and virus load, ERS 2010
13. M. Vareille, et al., Deficient innate immune antiviral response to infection with rhinoviruses in cystic fibrosis airway epithelial cells, ERS 2010
14. S. Stick, et al., Dysregulated inflammatory and apoptotic responses to human rhinovirus in primary airway cells from young patients with cystic fibrosis, ERS 2010
15. B.G. Cosio, et al., Microbiology of COPD exacerbations at hospital admission: The ECOS study, ERS 2010
16. L. Millares, et al., Specific immune response against Haemophilus influenzae in stable COPD, ERS 2010

 

Keyword: ATS 2010

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