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The Proceedings of the American Thoracic Society 4:611-617 (2007)
© 2007 The American Thoracic Society
doi: 10.1513/pats.200706-065TH
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The Interaction of Host and Pathogen Factors in Chronic Obstructive Pulmonary Disease Exacerbations and Their Role in Tissue Damage

Hatem Abusriwil1 and Robert A. Stockley1

1 The University of Birmingham and University Hospital Birmingham Foundation Trust, Birmingham, United Kingdom

Correspondence and requests for reprints should be addressed to Robert A. Stockley, M.D., D.Sc., F.R.C.P., Lung Investigation Unit, Nuffield House, Queen Elizabeth Hospital, Birmingham B15 2TH, UK. E-mail: r.a.stockley{at}bham.ac.uk

ABSTRACT

Inflammation plays a central role in the development and progression of chronic obstructive pulmonary disease (COPD). Host factors, such as proteinases and oxidants, have been implicated in causing tissue damage and amplifying the inflammatory process. During exacerbations of COPD, inflammation, oxidant stress, and many of these proteinases are increased. The role of bacteria in exacerbation remains unclear; however, many bacterial factors, such as proteases, surface proteins, lipopoly(oligo)saccharide, and pyocyanin, may also damage lung tissue either directly or by promoting the host inflammatory response. The interaction between host and bacterial factors is complex and both can cause similar damage, making it difficult to dissect the relative contribution of each factor. There have been few relevant studies in man; however, most of the available evidence relates to the importance of the host response. To resolve this issue, several steps are required. Lung secretions need to be collected from patients in the stable clinical state as well as during well defined exacerbations involving bacteria. The appropriate factors need to be identified in the secretions and require evidence that they are functionally active. Specific abrogation should then change the overall balance within the local environment, after which the administration of specific inhibitors/antagonists can be used to confirm that the factor being studied is central to the inflammatory cascade and subsequent tissue damage in patients. Finally, controlled clinical trials will be required to demonstrate that modifying inflammation influences long-term progression.

Key Words: bacterial • inflammation • COPD • lung damage

Chronic obstructive pulmonary disease (COPD) is an inflammatory condition with a slow, progressive deterioration (1). This course is interrupted by intermittent episodes of exacerbation, which tend to become more frequent as the severity of COPD increases (2). This may reflect the fact that more severe airflow obstruction makes the lung more sensitive to minor changes that may not have precipitated symptoms in a less severely affected individual. Alternatively, it is possible that the more lung damage that is present as airflow obstruction progresses, the more susceptible the lung becomes to infection.

It has been shown that exacerbations not only influence health status (3) and lead to increasing health care costs (4) and increased mortality (5), but also relate to the decline in lung function. Studies have indicated that the decline in FEV1 in patients having recurrent exacerbations is slightly greater than in those without (6), although it is possible that this is predominantly a feature of continuing smokers (7). In {alpha}1-antitrypsin deficiency, the decline in vital capacity has been related to the number of exacerbations, as indeed was the change in the carbon monoxide transfer factor (TLCO) (8). However, the fact that carbon monoxide transfer corrected for alveolar volume is not related to exacerbations provides supporting evidence that these episodes are related to bronchial as opposed to alveolar damage (8).

The role of pathogens in exacerbations is unclear. Viruses probably play a role, because, often, there are preceding upper respiratory tract symptoms suggesting a coryzal illness before lower airway symptoms (9). It is known that viruses can damage epithelial surfaces, and it has been argued that this may lead to subsequent bacterial infection through facilitated adherence to the damaged epithelium.

Bacteria are isolated during exacerbations in approximately 50% of episodes. Nevertheless, it has also been well recognized that 30–40% of patients with COPD and chronic mucus expectoration have viable bacteria present in the secretions, even in the stable state (10), calling in to question their role in the exacerbations. However, more recent studies have indicated that it is not just the presence of bacteria, but their numbers (11), acquisition of new strains (12), and probably interaction with viruses (13, 14) that relate to the features of exacerbation (see subsequent discussion).

Because bacteria release many factors with the potential to damage the airway, and host inflammatory responses can do the same, this raises the question of which causes the greatest injury. The purpose of the current review is to outline the potential of bacteria and the host in isolation to cause tissue damage, describe the interaction, and summarize the present or required evidence to determine the role of each.

BACTERIAL PRODUCTS

Evading Host Defenses and Colonization
Despite the inhalation of greater than 104 viable bacteria daily, the lower respiratory tract remains sterile in health. This is the result of a sophisticated host defense system that comprises bacteriostatic proteins (lysozyme, lactoferrin), bacteriocidal factors (β defensins), local immunity (secretory IgA), resident phagocytes (airway macrophages), and a tight epithelial lining with a sophisticated mucociliary clearance mechanism. Thus, in the presence of the healthy lung, the bacterial factors would have to disturb or circumvent these sophisticated mechanisms to establish airways colonization and cause infection and/or tissue damage. Patients with COPD have clear evidence of impaired mucociliary clearance (15) together with excess mucus production (which can provide a microenvironment for bacterial replication isolated from secondary host defenses). This combination facilitates colonization and infection, and, hence, potentially also facilitates tissue damage from bacterial factors.

A variety of such bacterial factors have been identified that can be implicated in tissue damage, although studies of respiratory pathogens have been relatively limited. Nontypable Haemophilus influenzae, Streptococcus pneumoniae, and Moraxella catarrhalis are the major pathogens colonizing the respiratory tract in COPD, although gram-negative bacteria, such as Pseudomonas aeruginosa, are more common in the later stages (16).

Table 1 outlines some of the potential bacterial factors that are able to disrupt host defenses and evade the host immune system. This includes the ability to promote adherence (flagella and pili), degrade complement and immunoglobulins (Igs; proteases), impair ciliary function and increase mucus secretion (proteases, pyocyanin, and pneumolysin), avoid phagocytosis (alginate, intracellular and intercellular invasion [17]), or damage the epithelial surface (Pseudomonas elastase, pyocyanin, and LPS).


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  		TABLE 1. PSEUDOMONAS AERUGINOSA, STREPTOCOCCUS PNEUMONIAE, AND HAEMOPHILUS INFLUENZAE VIRULENCE FACTORS*

 
Direct Tissue Damage
There is evidence, mainly from in vitro studies, to suggest that several virulence factors, such as proteases, LPS, and pyocyanin, can cause direct tissue injury and degrade structural proteins (Table 1). However, these findings may not reflect in vivo conditions where complex host–pathogen interactions occur (see subsequent discussion). Factors that may determine the bacterial contribution to causing direct tissue damage include: (1) stage of disease—bacterial products may play an important role in early stages of the infectious process before the neutralizing action of host antibodies has taken full effect (18); (2) bacterial load—it is possible that the larger the bacterial load, the more likely that direct cytotoxicity will occur (19); and, finally, (3) the type of infecting organism—certain bacterial species (e.g., P. aeroginosa) have a greater cytotoxic potential than others (20).

Indirect Tissue Damage
Once the key primary host defenses have been breached, secondary host defenses are recruited, enhancing the inflammatory state within the airway. Bacteria can potentially promote this inflammatory process by several mechanisms (21, 22). These include disruption of the protease–antiprotease balance by direct activation of host-derived proteases (23) and/or inactivation of their inhibitors (24, 25), and stimulation of macrophages and epithelial cells to generate and release proinflammatory mediators and neutrophil chemoattractants (26–31). Many bacterial species can cause epithelial cell apoptosis, including Streptococcus (32) and Pseudomonas (33). Bacteria can also induce neutrophil necrosis (34) with resultant release of proteinases and other proinflammatory mediators. Recent studies have suggested that apoptosis plays a role in the development of emphysema (35). However, the fact that exacerbations of COPD are limited to the bronchi and small airway suggests that this mechanism would not play a role in the development and progression of emphysema.

This complex bacteria–host interaction poses a problem in trying to dissect the role of bacterial from host factors in the direct generation of tissue damage in vivo, particularly during exacerbations, when both inflammation and bacterial load increases (see subsequent discussion).

HOST RESPONSES

Although primary defenses restrict bacterial colonization, they can be overwhelmed. The larger the initial bacterial innoculum, the more likely in situ replication will exceed the primary clearance mechanisms, and, at this point, a secondary defense process is initiated. The relationship between bacterial load and subsequent response has been shown clearly in animal experiments where low bacterial loads result in bacterial clearance, but loads in excess of 106 cfu/ml result in bacterial proliferation and an inflammatory host response (36). The host response is the result of a variety of neutrophil chemoattractants and other proinflammatory cytokines released from bacteria or macrophages and epithelial cells in response to bacteria or their products (Figure 1). The net result is protein leakage, resulting in transfer of Igs and complement from serum into the lung, and neutrophil recruitment, which will increase bacterial killing and removal.


Figure 1
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  		Figure 1. A diagrammatic presentation of some of the interactions of bacteria and their products with host defenses. Bacterial products can promote inflammatory responses by epithelial cells directly or via macrophage activation as a result of phagocytosis. The subsequent neutrophil recruitment and activation amplify the response. IL-8 = interleukin-8; LTB4 = leukotriene B4.

 
Studies in humans are more difficult than animal challenge models. However, they have shown that the secondary host defense response is activated in patients with bronchial disease once the bacterial load within the lung increases beyond 106 cfu/ml (37). Furthermore, the response is associated with an increase in proteinase activity within the airway, particularly involving neutrophil elastase (37) and an oxidant burden due to neutrophil activation (38). Recent studies have demonstrated a specific local and systemic host immune response to most common pathogens isolated during exacerbations (39–41), which provides further evidence to implicate bacteria in the pathogenesis of acute exacerbations (42).

HOST PRODUCTS

Lung inflammation is believed to be a central feature of the pathophysiology of COPD. The factors implicated include, neutrophil serine proteinases, oxidants, and metallo- and cysteine proteinases. Indeed, evidence exists that all of these factors play a role in tissue damage and, hence, are relevant to COPD. Emphysema can be caused by neutrophil serine proteinases, elastase, and proteinase 3, as well as the cysteine proteinase, cathepsin B. In addition, elastase, cathepsin G, and cathepsin B can all cause mucous gland hyperplasia. Elastase and cathepsin G have been shown to increase mucus secretion, and elastase decreases ciliary beat frequency and cleaves Igs and the C3bi receptor on neutrophils necessary for opsonophagocytosis (43). All of these latter factors affect host defenses, further reducing the ability of the lung to prevent colonization and infection.

Metalloproteinase knockout mice are susceptible to developing emphysema (44), and oxidants have been shown not only to cause tissue damage in vitro, but also to be proinflammatory (45). Many of these factors have been detected in the airway secretions (46), or the footprints of these processes have been found in secretions and the circulation (47).

INTERRELATIONSHIP AND EXACERBATIONS

Bacterial colonization has been shown to be associated with increased inflammation in the airway, although this is dependent on the bacterial load (37). During exacerbations of COPD, there is a general increase in inflammation, which is probably related mainly to bacterial episodes (11), bacterial species (37), and bacterial strains (48). During these episodes, host proteinases (49) and the oxidant burden (50) are increased. This may not be the case if the exacerbation is not bacterial in origin, although a recent study has suggested that neutrophilic inflammation may also occur in episodes thought to be primarily viral in origin (13).

The inflammation associated with exacerbations increases and subsequently decreases as the episode is resolved; this is associated with increased isolation and increased bacterial load at the beginning, which returns to a baseline state as the episode resolves. Previous study by our group has identified a subset of patients who produce mucoid sputum during exacerbation and had a similar and low bacterial load during exacerbation and after recovery. These patients were different from those with purulent sputum during the episode, who had a significant increase in bacterial load during exacerbation (11). Studies by Sethi and colleagues have suggested that phenotypic changes in bacteria occur at these episodes (48). This may explain the observed increase in bacterial numbers reported in other studies (11, 14), as they escape the background immune response. However, a more recent longitudinal study by Sethi and colleagues suggested that bacterial load is not related to the occurrence of exacerbation if the acquisition of new strains is taken into account (51); however, in a subset of exacerbations associated with new strains of H. influenzae and M. catarrhalis, the bacterial load did increase some threefold. The study, unfortunately, did not characterize the episodes according to sputum purulence. The complexities of host–bacteria interactions require further exploration and extensive characterization of exacerbation episodes to further our understanding of the pathogenesis of acute exacerbations.

Because exacerbations are related to a greater decline in lung function, it could be a result of either the bacterial factors or factors released as part of the host response. Resolution of the episode is associated with the reduction in both bacteria (and hence their products) and the host inflammatory response and its products. However, few studies have been undertaken to dissect this process in details. Where studies have been undertaken, the proteinase burden (for instance, in Pseudomonas infection) is probably predominantly from the host (20). Although careful in vitro studies have confirmed that Pseudomonas (52), Haemophilus (53), and streptococcal (54) products reduce ciliary beat frequency in vitro, they may be a minor factor in vivo. Studies using secretions from infected airways reduced the ciliary beat frequency. This was abrogated by the addition of {alpha}1-antitrypsin, which inhibits the neutrophil serine proteinases (55), suggesting that they were the major cause and not bacterial products (Figure 2). Furthermore, Venaille and colleagues (20) studied the effect of sputum from patients with and without cystic fibrosis on epithelial detachment in vitro. Detachment (a proteinase effect) was induced by P. aeruginosa–infected sputum and by pure isolates of P. aeruginosa and neutrophils. However, protease inhibition studies to determine the profile in the Pseudomonas-infected sputum indicated a predominant neutrophil profile (20). These studies suggest that protease activity in airway secretions is mainly derived from the host, and supports other studies demonstrating insignificant proteolytic activity of Pseudomonas elastase in the presence of neutrophil elastase (56, 57). Thus, as both Pseudomonas protease and neutrophil elastase, in isolation, can cause epithelial damage (58), these results would suggest that the host factors predominate.


Figure 2
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  		Figure 2. The effect of lung secretion on ciliary beat frequency is shown over time compared with control. The addition of {alpha}1-antitrypsin (AT) abrogates the effect (reprinted by permission from Reference 55).

 
It is clear that the interactions are complex. For instance, the host proteases can all activate each other and inactivate their specific inhibitors (Figure 3). The predominant end result depends on the balance of these interactions, inhibitor production, and enzyme release. This is further complicated by oxidants released from the host inflammation or bacteria that can inactivate the inhibitors, thereby releasing further enzyme activity. In addition, bacterial proteinases can also inactivate the inhibitors with the same shift in enzyme–inhibitor balance. All these processes would be enhanced during an exacerbation of bacterial origin. Therefore, dissection of the processes requires a complex series of approaches.


Figure 3
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  		Figure 3. Protease/antiprotease cascade showing the potential interaction with bacterially derived proteases or oxidants. MMP = matrix metalloproteinase; TIMP = tissue inhibitor of metalloproteinases; SLPI = secretory leukocyte proteinase inhibitor; TNF = tumor necrosis factor. Modified by permission from Reference 96.

 
First, it is important to detect whether the enzymes, inhibitors, or oxidants are present (immune assays and evidence of protein oxidation); second, it is necessary to determine whether they are active (specific substrates or inactivating antibodies or chemicals); and, finally, if they are abrogated (specific antagonists), does the overall balance shift? Once this last stage is reached, it should be possible to develop therapeutic antagonists to answer the final question in proof-of-concept studies: namely, is the host–bacterial factor responsible for lung damage/progression in COPD and its exacerbations?

CONCLUSIONS

In conclusion, there is evidence that host enzymes are important in the pathophysiology of COPD. The interaction of the host and bacteria is complex (Figure 4), and both bacterial and host factors have the potential to amplify this process. However, most of the in vivo evidence currently relates to the importance of the host response, but new assays are needed to dissect the potential role of bacteria and/or host. The final step will be careful in vivo studies to resolve this issue.


Figure 4
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  		Figure 4. Host–pathogen interaction. Bacteria produce several virulence factors that are involved in tissue destruction, either through direct action, or indirectly by activation of host inflammatory response. Bacteria have the ability to evade the host immune system and colonize the airways, for example, by cleaving complement components and immunoglobulins and disrupting the mucociliary clearance. This contributes to the persistent nature of inflammation and progressive structural damage in chronic lung diseases, which in turn leads to even more bacterial colonization and a self-perpetuated cycle of inflammation.

 
FOOTNOTES

Conflict of Interest Statement: H.A. was sponsored to attend the European Respiratory Society meeting by Allen & Hanbury in 2006. R.A.S. has received funding to attend international conferences from Boehringer Ingelheim and Talecris and speaking at conferences organized by GlaxoSmithKline (GSK) and AstraZeneca (AZ). He has served on advisory panels for Roche, GSK and Merck, Sharp & Dohme ($5,000 in 2006). He is in receipt of noncommercial grants from AZ (£30,000 in 2006) and Talecris (£317,000 in 2006).

(Received in original form June 1, 2007; accepted in final form July 26, 2007)

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