Targeting the Heme Oxygenase 1/Carbon Monoxide Pathway to Resolve Lung Hyper-Inflammation and Restore a Regulated Immune Response in Cystic Fibrosis

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 (MFs) are key regulators of immune response and host defense. We and others have shown that, in CF, MFs are hyper-inflammatory and exhibit reduced bactericidal activity. Thus, MFs 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/MFs 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 CFaffected 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.

Dual Carbonic Anhydrase IX/XII Inhibitors and Carbon Monoxide Releasing Molecules Modulate LPS-Mediated Inflammation in Mouse Macrophages

“…The effects of hyper-inflammation in inflammatory diseases are largely attributed to the impairment of several signaling pathways associated with cell responses toward oxidative stress, including the Nrf2/inducible heme oxygenase-1 (HO-1)/CO molecular axis [ 8 , 9 ]. Under oxidative stress, the HO-1 enzyme degrades heme group, leading to the production of potent antioxidant, anti-inflammatory, and bactericidal mediators (biliverdin, bilirubin, and CO) and monocytes/macrophages rely on abundant induction of the HO-1/CO pathway [ 10 ]. The overexpression of HO-1 during altered intracellular redox state confirms its role as an important component of stress response and suggests the cytoprotective effects exerted by CO, acting as gasotransmitter along with NO and H 2 S [ 11 ].…”

Carbon monoxide-releasing molecules inhibit the cystic fibrosis transmembrane conductance regulator Cl−channel

“…Second, the present results and other data (2) suggest that CO should be used with caution to treat lung inflammation. Based on its wide ranging beneficial effects, including dampening inflammation, reducing oxidative stress and strengthening host defense mechanisms [for review, see (14,43)], CO has been investigated as a therapy for lung inflammation in acute respiratory distress syndrome (16) and chronic obstructive pulmonary disease (COPD) (3). Like COPD (51), CF lung disease is characterized by persistent bacterial infection and exaggerated inflammatory responses (54).…”

A Novel Class of Dual-Acting DCH-CORMs Counteracts Oxidative Stress-Induced Inflammation in Human Primary Tenocytes

“…HO-1 metabolites, including CO, are important in restoring redox homeostasis and resolution of inflammation, and it has been widely demonstrated that the HO-1/CO axis can help to prevent cellular and tissue damage. Therefore, the manipulation of the HO-1/CO system is an attractive strategy to treat conditions linked to oxidative-stress-induced inflammation, such as lung hyper-inflammation in cystic fibrosis, sepsis and modulation of chronic pain [ 2 , 3 , 4 , 5 , 6 , 7 ]. The chemistry of CO is unique: unlike NO and H 2 S that react indiscriminately with intracellular targets, CO offers the advantage of binding only to transition metals in a low oxidation state.…”