Abstract
In individuals with cystic fibrosis (CF), lung hyper-inflammation starts early in life and is perpetuated by mucus obstruction and persistent bacterial infections. The continuous tissue damage and scarring caused by non-resolving inflammation leads to bronchiectasis and, ultimately, respiratory failure. Macrophages (MΦs) are key regulators of immune response and host defense. We and others have shown that, in CF, MΦs are hyper-inflammatory and exhibit reduced bactericidal activity. Thus, MΦs contribute to the inability of CF lung tissues to control the inflammatory response or restore tissue homeostasis. The non-resolving hyper-inflammation in CF lungs is attributed to an impairment of several signaling pathways associated with resolution of the inflammatory response, including the heme oxygenase-1/carbon monoxide (HO-1/CO) pathway. HO-1 is an enzyme that degrades heme groups, leading to the production of potent antioxidant, anti-inflammatory, and bactericidal mediators, such as biliverdin, bilirubin, and CO. This pathway is fundamental to re-establishing cellular homeostasis in response to various insults, such as oxidative stress and infection. Monocytes/MΦs rely on abundant induction of the HO-1/CO pathway for a controlled immune response and for potent bactericidal activity. Here, we discuss studies showing that blunted HO-1 activation in CF-affected cells contributes to hyper-inflammation and defective host defense against bacteria. We dissect potential cellular mechanisms that may lead to decreased HO-1 induction in CF cells. We review literature suggesting that induction of HO-1 may be beneficial for the treatment of CF lung disease. Finally, we discuss recent studies highlighting how endogenous HO-1 can be induced by administration of controlled doses of CO to reduce lung hyper-inflammation, oxidative stress, bacterial infection, and dysfunctional ion transport, which are all hallmarks of CF lung disease.
Highlights
The hallmarks of cystic fibrosis (CF) lung disease are mucus obstruction, chronic hyper-inflammation, chronic infections, and excessive oxidative stress, which severely damage lung tissue over time and lead to lung failure
We have shown that the defective induction of Heme oxygenases (HO)-1 is due to blunted activation of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway downstream of toll-like receptor 4 (TLR4) activation in MFs from CF mouse models and patients with CF
We found that HO-1 does not compartmentalize to the cell surface in CF MFs, but rather accumulates intracellularly due to decreased caveolin 1 (Cav1) expression (Zhang et al, 2013)
Summary
The hallmarks of cystic fibrosis (CF) lung disease are mucus obstruction, chronic hyper-inflammation, chronic infections, and excessive oxidative stress, which severely damage lung tissue over time and lead to lung failure. Despite the role of inflammation in CF lung disease, corticosteroids, or highdose ibuprofen are the only approved long-term treatments for CF airway inflammation Both treatments are often poorly tolerated (Mogayzel et al, 2013; Cantin et al, 2015). When treating CF lung disease, a fine balance must be maintained between dampening the pro-inflammatory response and preserving the host defense against microorganisms (Konstan et al, 2014). This situation calls for novel therapeutic targets, which allow a potent anti-inflammatory/antimicrobial host defense followed by restoration of lung tissue homeostasis. We will discuss: (1) how the shortcomings of CF lung immunity perpetuate inflammatory signaling and poor bacterial clearance; (2) the role of the HO-1/CO signaling pathway; and (3) the potential of CO-based therapy to reduce lung hyperinflammation, counteract oxidative stress, and improve bacterial clearance, restoring lung homeostasis in CF lung disease
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