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American Journal of Respiratory Cell and Molecular Biology. Vol. 37, pp. 129-130, 2007
© 2007 American Thoracic Society
DOI: 10.1165/rcmb.2007-0002ED

Editorial

To Live and Die in the LA (Lung Airway)

Mode of Neutrophil Death and Progression of Chronic Obstructive Pulmonary Disease

Naoto Minematsu

University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania and Department of Medicine, Keio University, Tokyo, Japan

Steven D. Shapiro

University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania

In this issue of the Journal, Naylor and colleagues show that in chronic obstructive pulmonary disease (COPD), infection with Haemophilus influenza leads to neutrophil necrosis with release of granule contents including neutrophil elastase (NE). These findings integrate old and new concepts regarding exacerbations and lung destruction in COPD, leading to a unified mechanism that links infection with disease progression (Figure 1).


Figure 1
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  		Figure 1. Neutrophil fate and effect on lung damage. After neutrophil influx into the lung, the short-lived neutrophil will die and either undergo (1) apoptosis with subsequent phagocytosis by macrophages leading to an anti-inflammatory reparative response, (2) primary or secondary necrosis followed by a destructive, proinflammatory process. Note that infection would lead to primary necrosis while failure of a macrophage to take up an apoptotic neutrophil would cause secondary necrosis.

 
The role of the neutrophil and NE in COPD ushered in the modern era of COPD pathogenesis forming the basis of the elastase:antielastase hypothesis proposed in the early 1960s. Later, with support from newer animal models of emphysema, we began to appreciate the role of the macrophage and its complement of matrix metalloproteinases (such as MMP-9 and MMP-12) in promoting lung destruction. In addition to destruction of the extracellular matrix, we now also appreciate the role of cellular death in emphysema. Despite these newer advances, NE remains a potent elastase that if expressed and free at high levels in the lung is bound to cause lung destruction. Moreover, NE is also a potent secretagogue enhancing mucus production.

Traditionally, we thought that cigarette smoke leads to acute influx of short-lived neutrophils into the lung, followed by release of free NE, overwhelming inhibitors in local microenvironments, leading to lung destruction. While likely true, we overestimated the amount of free NE released from intact neutrophils. In fact, activated neutrophils only secrete only 2% of their granular contents of NE and displace 12% to the cell surface (1). Neutrophils may release more NE after "frustrated phagocytosis," but hard evidence for this is lacking.

Hence, it is not the life but the death of the neutrophil that seems to determine its destructive capacity. A clean, altruistic apoptotic death, followed by efficient removal by macrophages, protects the lung from harmful neutrophil products. But, if the macrophage is unable to clear a neutrophil, the cell would undergo secondary necrosis and release large amounts of NE as well as other destructive oxidants and proteinases. Or, as in the case here, the neutrophil is induced by bacteria to undergo necrosis directly, in which case neutrophil contents would also be released. There is ample evidence in the literature supporting the destructive capacity of the necrotic neutrophil. A beautiful example comes from a study of bleomycin injury in CD44-deficient mice. In that model, CD44-deficient macrophages were unable to engulf neutrophils, resulting in enhanced neutrophilia, increased fibrosis, and greater mortality (2).

While macrophages, which also accumulate in lungs of patients with COPD, are proteinase-producing arsenals themselves capable of lung destruction, they also serve critical host functions. These professional phagocytes are the first line of alveolar defense if pathogens escape removal from the airways. They also remove cellular and matrix debris and remodel the extracellular matrix to maintain lung structure. Macrophage clearance of neutrophils not only limits damage but also inhibits inflammation in general.

Macrophage phagocytosis has been reported to be impaired in response to cigarette smoke (3, 4) as well as ex-smokers with COPD (5, 6). Normally macrophages recognize molecular alterations of apoptotic cells such as asymmetric distribution of phosphatidylserine (PS) on the outer leaflets, as well as other surface and bridging molecules (reviewed in Refs. 7, 8). Phagocytes tethering apoptotic cells subsequently ruffle their plasma membrane and internalize the apoptotic cells and undergo an orchestrated series of molecular events, including inhibition of RhoA and activation of Rac-1, leading to degradation of the apoptotic cell. Additional downstream events include production of anti-inflammatory cytokines, including IL-10 and TGF-beta (9, 10), secretory leukocyte protease inhibitor (11), and release of reparative growth factors (12, 13). Hence, removal of apoptotic, but not necrotic cells limits further inflammation and tissue damage, and initiates repair. This all occurs very quickly, making it difficult to visualize dying cells in histologic specimens even in the presence of massive cell death as occurs in acute pneumonia (14). How smoking and COPD impair neutrophil uptake is not well delineated, but, may in part involve cleavage of macrophage recognition molecules by NE, impairing apoptotic cell uptake (15). Bridging molecules, SP-A and -D are also decreased in the lungs of smokers (16), also potentially contributing to the defect. Of note, statins (17) and macrolides (18) were recently reported to enhance phagocytosis. This might help explain their anti-inflammatory properties and provide a mechanism of action to be pursued as therapy for COPD.

The neutrophilic response to cigarette smoke is clearly a false alarm with detrimental consequences. However, neutrophils are required to remove pathogens, particularly during acute airway infections that occur in patients with COPD. It has been very difficult to determine whether exacerbations themselves contribute to decline in lung function, although most evidence does point to an additional loss of FEV1 with each exacerbation (19). It is also believed that the host response to a greater degree than the inciting infection is responsible for the lung damage. However, strategies to prevent neutrophils from gaining access to the infected airway seem riskier than removing the neutrophil quickly after pathogen clearance. The findings in this manuscript suggest that this might be difficult since H. influenza leads to neutrophil necrosis. A better understanding of the apoptotic versus necrotic response could lead to strategies to prevent necrosis and clear bacteria. In the meantime, limiting excess inflammation might be the simplest therapeutic strategy for COPD.

Footnotes

Conflict of Interest Statement: Neither author has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

References

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