Nano-based rescue of dysfunctional autophagy in chronic obstructive lung diseases

ABSTRACT

Introduction: ΔF508-CFTR (cystic fibrosis transmembrane conductance regulator) is a common CF-mutation that is known to induce oxidative-inflammatory stress through activation of reactive oxygen species (ROS), which induces autophagy-impairment resulting in accumulation of CFTR in aggresome-bodies. Cysteamine, the reduced form of cystamine, is a FDA-approved drug that has anti-oxidant, anti-bacterial, and mucolytic properties. This drug has been shown in a recent clinical trial to decrease lung inflammation and improve lung function in CF patients by potentially restoring autophagy and allowing CFTR to be trafficked to the cell membrane.

Areas covered: The delivery of cysteamine to airway epithelia of chronic subjects prerequisite the need for a delivery system to allow rescue of dysfunctional autophagy.

Expert opinion: We anticipate based on our ongoing studies that PLGA-PEG- or Dendrimer-mediated cysteamine delivery could allow sustained airway delivery over standard cysteamine tablets or delay release capsules that are currently used for systemic treatment. In addition, proposed nano-based autophagy induction strategy can also allow rescue of cigarette smoke (CS) induced acquired-CFTR dysfunction seen in chronic obstructive pulmonary disease (COPD)-emphysema subjects. The CS induced acquired-CFTR dysfunction involves CFTR-accumulation in aggresome-bodies that can be rescued by an autophagy-inducing antioxidant drug, cysteamine. Moreover, chronic CS-exposure generates ROS that induces overall protein-misfolding and aggregation of ubiquitinated-proteins as aggresome-bodies via autophagy-impairment that can be also be resolved by treatment with autophagy-inducing antioxidant drug, cysteamine.

KEYWORDS:

• Nanoparticle
• autophagy
• cystic fibrosis
• COPD
• emphysema
• cigarette smoke
• Pseudomonas aeruginosa
• exacerbation

Article highlights

• ROS activation induces autophagy-impairment in CF and COPD-emphysema

• Autophagy inducing anti-oxidant, cyateamine inhibits ROS-mediated autophagy-impairment

• Genetic and cigarette smoke induced CFTR dysfunction impairs autophagy

• Nano-based airway delivery of cysteamine allows rescue of autophagy-impairment in chronic obstructive lung diseases

• Nano-based-cysteamine also possess anti-bacterial and mucolytic properties for bypassing the airway defense during delivery

This box summarizes key points contained in the article.

Declaration of interest

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

N Vij was supported by FAMRI (YCSA_082131) and NIH (U54CA141868) grants during this period. The funders had no role in design, format, decision to publish or preparation of manuscript.