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State of the art: why do the lungs of patients with cystic fibrosis become infected and why can't they clear the infection?

Chmiel JF, Davis PB - Respir. Res. (2003)

Bottom Line: Cystic Fibrosis (CF) lung disease, which is characterized by airway obstruction, chronic bacterial infection, and an excessive inflammatory response, is responsible for most of the morbidity and mortality.In response to increased IL-8 and leukotriene B4 production, neutrophils infiltrate the lung where they release mediators, such as elastase, that further inhibit host defenses, cripple opsonophagocytosis, impair mucociliary clearance, and damage airway wall architecture.Until a cure is discovered, further investigations into therapies that relieve obstruction, control infection, and attenuate inflammation offer the best hope of limiting damage to host tissues and prolonging survival.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pediatrics, Case Western Reserve University School of Medicine at Rainbow Babies and Children's Hospital, Cleveland, OH, USA. jxc34@po.cwru.edu <jxc34@po.cwru.edu>

ABSTRACT
Cystic Fibrosis (CF) lung disease, which is characterized by airway obstruction, chronic bacterial infection, and an excessive inflammatory response, is responsible for most of the morbidity and mortality. Early in life, CF patients become infected with a limited spectrum of bacteria, especially P. aeruginosa. New data now indicate that decreased depth of periciliary fluid and abnormal hydration of mucus, which impede mucociliary clearance, contribute to initial infection. Diminished production of the antibacterial molecule nitric oxide, increased bacterial binding sites (e.g., asialo GM-1) on CF airway epithelial cells, and adaptations made by the bacteria to the airway microenvironment, including the production of virulence factors and the ability to organize into a biofilm, contribute to susceptibility to initial bacterial infection. Once the patient is infected, an overzealous inflammatory response in the CF lung likely contributes to the host's inability to eradicate infection. In response to increased IL-8 and leukotriene B4 production, neutrophils infiltrate the lung where they release mediators, such as elastase, that further inhibit host defenses, cripple opsonophagocytosis, impair mucociliary clearance, and damage airway wall architecture. The combination of these events favors the persistence of bacteria in the airway. Until a cure is discovered, further investigations into therapies that relieve obstruction, control infection, and attenuate inflammation offer the best hope of limiting damage to host tissues and prolonging survival.

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Impact of mutant cystic fibrosis transmembrane conductance regulator (CFTR) on cellular physiology. Mutant CFTR promotes initial bacterial infection by upregulating epithelial cell adhesion molecules for bacteria such as asialo-GM1 and by decreasing production of innate host defense molecules such as nitric oxide (NO). Defects in CFTR also lead to increased sodium absorption through the epithelial sodium channel (ENaC) and decreased chloride secretion. Water follows its concentration gradient and results in decreased depth of airway surface liquid. Bacterial persistence is promoted by alterations in airway wall architecture, impaired host defense mechanisms, an excessive inflammatory response, and adaptations made by the bacteria to the microenvironment of the cystic fibrosis airway.
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Figure 1: Impact of mutant cystic fibrosis transmembrane conductance regulator (CFTR) on cellular physiology. Mutant CFTR promotes initial bacterial infection by upregulating epithelial cell adhesion molecules for bacteria such as asialo-GM1 and by decreasing production of innate host defense molecules such as nitric oxide (NO). Defects in CFTR also lead to increased sodium absorption through the epithelial sodium channel (ENaC) and decreased chloride secretion. Water follows its concentration gradient and results in decreased depth of airway surface liquid. Bacterial persistence is promoted by alterations in airway wall architecture, impaired host defense mechanisms, an excessive inflammatory response, and adaptations made by the bacteria to the microenvironment of the cystic fibrosis airway.

Mentions: The post-translational modification of cell surface and secreted molecules may be altered to facilitate binding of P. aeruginosa and other infecting agents. Several mechanisms for retention of bacteria in the airways of patients with CF have been proposed. Asialo-GM1, a ligand for P. aeruginosa, S. aureus, and H. influenzae, is increased on CF airway epithelial cells [28], sufficient to explain a two-fold increase in bacterial binding [29], a modest change, but one which could become important over time. Some investigators have questioned the importance of adherence, since histopathologic examination reveals relatively few bacteria in apposition to the epithelial surface, suggesting that the dense mucus layer may prevent access [30,31]. However, these studies were performed on samples taken at autopsy or transplantation, and thus represent end-stage lung disease. At this point, bacteria have adapted to their environment by a downregulation of the genes for pilin and flagelin, two important epithelial adhesins. Even at this late stage in the disease process, however, other bacteria, notably Burkholderia cepacia, can penetrate the mucus layer and even the epithelial barrier [32], suggesting that the dense mucus is not an absolute barrier to epithelial access. Earlier in the disease process, however, when pilin and flagelin are expressed by P. aeruginosa, the classical infectious disease paradigm of adherence followed by infection may still be valid. In addition, even if surface binding of bacteria is not quantitatively important in the establishment of infection, it may be important for the initiation of an exuberant inflammatory response [33]. The binding of pilin to asialo-GM1 activates the pro-inflammatory transcription factor NF-κB and induces production of the neutrophil chemoattractant IL-8 [34,35]. Flagelin, like pilin, extends from the bacterial cell surface and promotes P. aeruginosa retention in the airways of patients with CF by binding to mucin oligosaccharides via flagellar cap protein FliD [36,37] and to epithelial cell oligosaccharides where it stimulates the production of pro-inflammatory cytokines [38]. Specific attachment of bacteria, combined with the putative compromise of mucociliary clearance as a direct result of the salt transport defect, promotes retention of bacteria in the mucus of the airways of patients with CF and allows them to multiply there. The relationship between mutant CFTR and these pathophysiologic processes is shown in Figure 1.


State of the art: why do the lungs of patients with cystic fibrosis become infected and why can't they clear the infection?

Chmiel JF, Davis PB - Respir. Res. (2003)

Impact of mutant cystic fibrosis transmembrane conductance regulator (CFTR) on cellular physiology. Mutant CFTR promotes initial bacterial infection by upregulating epithelial cell adhesion molecules for bacteria such as asialo-GM1 and by decreasing production of innate host defense molecules such as nitric oxide (NO). Defects in CFTR also lead to increased sodium absorption through the epithelial sodium channel (ENaC) and decreased chloride secretion. Water follows its concentration gradient and results in decreased depth of airway surface liquid. Bacterial persistence is promoted by alterations in airway wall architecture, impaired host defense mechanisms, an excessive inflammatory response, and adaptations made by the bacteria to the microenvironment of the cystic fibrosis airway.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC203156&req=5

Figure 1: Impact of mutant cystic fibrosis transmembrane conductance regulator (CFTR) on cellular physiology. Mutant CFTR promotes initial bacterial infection by upregulating epithelial cell adhesion molecules for bacteria such as asialo-GM1 and by decreasing production of innate host defense molecules such as nitric oxide (NO). Defects in CFTR also lead to increased sodium absorption through the epithelial sodium channel (ENaC) and decreased chloride secretion. Water follows its concentration gradient and results in decreased depth of airway surface liquid. Bacterial persistence is promoted by alterations in airway wall architecture, impaired host defense mechanisms, an excessive inflammatory response, and adaptations made by the bacteria to the microenvironment of the cystic fibrosis airway.
Mentions: The post-translational modification of cell surface and secreted molecules may be altered to facilitate binding of P. aeruginosa and other infecting agents. Several mechanisms for retention of bacteria in the airways of patients with CF have been proposed. Asialo-GM1, a ligand for P. aeruginosa, S. aureus, and H. influenzae, is increased on CF airway epithelial cells [28], sufficient to explain a two-fold increase in bacterial binding [29], a modest change, but one which could become important over time. Some investigators have questioned the importance of adherence, since histopathologic examination reveals relatively few bacteria in apposition to the epithelial surface, suggesting that the dense mucus layer may prevent access [30,31]. However, these studies were performed on samples taken at autopsy or transplantation, and thus represent end-stage lung disease. At this point, bacteria have adapted to their environment by a downregulation of the genes for pilin and flagelin, two important epithelial adhesins. Even at this late stage in the disease process, however, other bacteria, notably Burkholderia cepacia, can penetrate the mucus layer and even the epithelial barrier [32], suggesting that the dense mucus is not an absolute barrier to epithelial access. Earlier in the disease process, however, when pilin and flagelin are expressed by P. aeruginosa, the classical infectious disease paradigm of adherence followed by infection may still be valid. In addition, even if surface binding of bacteria is not quantitatively important in the establishment of infection, it may be important for the initiation of an exuberant inflammatory response [33]. The binding of pilin to asialo-GM1 activates the pro-inflammatory transcription factor NF-κB and induces production of the neutrophil chemoattractant IL-8 [34,35]. Flagelin, like pilin, extends from the bacterial cell surface and promotes P. aeruginosa retention in the airways of patients with CF by binding to mucin oligosaccharides via flagellar cap protein FliD [36,37] and to epithelial cell oligosaccharides where it stimulates the production of pro-inflammatory cytokines [38]. Specific attachment of bacteria, combined with the putative compromise of mucociliary clearance as a direct result of the salt transport defect, promotes retention of bacteria in the mucus of the airways of patients with CF and allows them to multiply there. The relationship between mutant CFTR and these pathophysiologic processes is shown in Figure 1.

Bottom Line: Cystic Fibrosis (CF) lung disease, which is characterized by airway obstruction, chronic bacterial infection, and an excessive inflammatory response, is responsible for most of the morbidity and mortality.In response to increased IL-8 and leukotriene B4 production, neutrophils infiltrate the lung where they release mediators, such as elastase, that further inhibit host defenses, cripple opsonophagocytosis, impair mucociliary clearance, and damage airway wall architecture.Until a cure is discovered, further investigations into therapies that relieve obstruction, control infection, and attenuate inflammation offer the best hope of limiting damage to host tissues and prolonging survival.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pediatrics, Case Western Reserve University School of Medicine at Rainbow Babies and Children's Hospital, Cleveland, OH, USA. jxc34@po.cwru.edu <jxc34@po.cwru.edu>

ABSTRACT
Cystic Fibrosis (CF) lung disease, which is characterized by airway obstruction, chronic bacterial infection, and an excessive inflammatory response, is responsible for most of the morbidity and mortality. Early in life, CF patients become infected with a limited spectrum of bacteria, especially P. aeruginosa. New data now indicate that decreased depth of periciliary fluid and abnormal hydration of mucus, which impede mucociliary clearance, contribute to initial infection. Diminished production of the antibacterial molecule nitric oxide, increased bacterial binding sites (e.g., asialo GM-1) on CF airway epithelial cells, and adaptations made by the bacteria to the airway microenvironment, including the production of virulence factors and the ability to organize into a biofilm, contribute to susceptibility to initial bacterial infection. Once the patient is infected, an overzealous inflammatory response in the CF lung likely contributes to the host's inability to eradicate infection. In response to increased IL-8 and leukotriene B4 production, neutrophils infiltrate the lung where they release mediators, such as elastase, that further inhibit host defenses, cripple opsonophagocytosis, impair mucociliary clearance, and damage airway wall architecture. The combination of these events favors the persistence of bacteria in the airway. Until a cure is discovered, further investigations into therapies that relieve obstruction, control infection, and attenuate inflammation offer the best hope of limiting damage to host tissues and prolonging survival.

Show MeSH
Related in: MedlinePlus