Halt Inflammation! Friend or Foe?

At the recent UK Cystic Fibrosis (CF) conference in Manchester, Professor Stuart Elborn gave a talk highlighting the change in understanding of the pulmonary microbiome, in health and disease and the implications for CF therapy. Originally the lung was thought of as a sterile environment, however, in the last decade with new DNA-based sequencing detection techniques, it has shown an unappreciated complexity in the bacterial microbiome of the respiratory tract (Figure 1) akin to the well-established Gut microflora paradigm. The healthy lung has a plethora of bacteria which help maintain a healthy airway, this homeostasis in chronic lung diseases however, is upset and shifts to an overgrowth of anaerobic Proteobacteira and Actinobacteria, (dysbiosis) which can lead to a cycle of infection, airway obstruction and uncontrolled inflammation as seen in CF. These findings have further extended an already growing list of “emerging CF pathogens,” but this raises interesting questions not only about exactly which microbes contribute to CF lung disease, but also about how the complex CF spectrum of microbial communities respond to antibiotics currently in use and under evaluation (Chmiel et al, 2014).

Roy 25-11-2015 Figure 1

Figure 1 Bacterial dysbiosis during chronic lung disorders. a | In healthy individuals, the composition of the airway microbiota is diverse and well balanced. Chronic lung disorders such as asthma, chronic obstructive pulmonary disease (COPD) and its exacerbations, and cystic fibrosis are accompanied by bacterial dysbiosis, which is due to the outgrowth of certain bacteria. Patients with asthma and COPD have many similarities in the bacteria causing dysbiosis. b | Bacterial dysbiosis during asthma is caused by an outgrowth of the Proteobacteria phylum and a shift in the proportion of Streptococci in the Firmicutes phylum. c | In patients with COPD, bacterial communities show an increase in Staphylococci and Streptococci, in addition to an outgrowth of the whole Proteobacteria phylum. d | Shifts in bacterial communities in the lungs of patients with cystic fibrosis are of a slightly different nature. As in asthma and COPD, Proteobacteria outgrow in the lungs of patients with cystic fibrosis. However, no changes in the Firmicutes phylum have been detected, whereas Actinobacteria are clearly overrepresented (Marsland and Gollwitzer, 2014)

In CF, gene mutations in CFTR leads to loss of function in CFTR on the epithelial apical membrane, meaning chloride and bicarbonate ions can no longer be secreted in to the airways. As a consequence of this, increased amounts of Na+ are absorbed into the cell, with Cl following through the paracellular pathway. Subsequently water is drawn from the airway surface layer (ASL) into the cells. This depletion of water from the ASL results in (i) increased mucus concentration, (ii) flattening of the cilia, and (iii) adhesion of the mucus layer to the airway surface (Buchanan et al 2009). The environment produced as a consequence is rich in thick sticky mucus and provides the perfect milieu for colonization and propagation of bacteria such as Pseudomonas aeruginosa and Staphylococcus aureus. Infection with the gram-positive organisms P. aeruginosa, S. aureus in the CF lung are associated with poorer clinical outcomes, such as rapid lung function decline, increased risk of pulmonary exacerbation, and greater rates of mortality or need for lung transplantation. Infections by both Gram-positive and Gram-negative bacteria aggravate the underlying mutations in the CF lung by exaggerating the host’s pro-inflammatory response e.g. increased levels of inflammatory cytokines, catecholamines, temperature, glucose and free ATP; along with bronchoconstriction altering regional oxygen concentrations and pH. With acute mucus production and vascular permeability this increases local nutrient supply and airway mucus also introduces further gradients of local anoxia and hyperthermia, all of which selectively favour the growth of the CF specific lung pathogens of S. aureus and P.aeruginosa (Dickson et al., 2014). This causes the recruitment of additional neutrophils to the airways resulting in further release of pro-inflammatory mediators, which leads to the self-perpetuating cycles of airway obstruction, infection, and inflammation (Figure 2).

Roy 25-11-2015 Figure 2

Figure 2. A model for cystic fibrosis (CF) lung disease pathophysiology. According to this model, defective ion and fluid transport due to a CFTR mutation results in inadequate clearance of mucus and the material it traps in CF airways. The retained material results in a cycle of airways obstruction, inflammation, and infection (Hoffman & Ramsey 2012).

With the promise of the new CF therapies in the next decade, i.e. CFTR potentiators and CFTR correctors for all CF patients, along with the existing therapies such as Pulmozyme, mannitol and hypertonic saline, it is likely that most patients will soon be able to maintain improved lung function and nutritional status well into adulthood.

As our understanding of the dynamics of airway bacterial ecology continues to expand, so too will the opportunities to develop novel strategies to better manage airway dysbiosis in CF. The CF airway should now be considered an integrated microbial community, rather than the domain of a few key pathogens, with the future focus on improving and maintaining a healthy bacterial community balance; through the specific killing of the ‘bad bugs’, but also research and develop improved therapies of ASL hydration and therefore improve muco-ciliary clearance which will return the lung to homeostasis.

Blog written by Roy Fox

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