The Lung-Brain Axis in Chronic Obstructive Pulmonary Disease-Associated Neurocognitive Dysfunction: Mechanistic Insights and Potential Therapeutic Options

Abstract

Chronic obstructive pulmonary disease (COPD) ranks as the third leading cause of global mortality, affecting 210 million individuals worldwide. Notably, 60% of COPD patients experience comorbid neurocognitive disorders. Importantly, patients with neurocognitive dysfunction often exhibit poor adherence to therapeutic interventions and medications, exacerbating their COPD morbidity and increasing hospitalization rates and mortality risk. This review explores the potential lung-brain axis in COPD, emphasizing that oxidative stress and inflammatory responses in the lungs can spread to the systemic circulation, thereby regulating in the blood-brain barrier (BBB) permeability and contributing to brain dysfunction. In addition, the role of hormone-based hypothalamic-pituitary-adrenal (HPA) axis in COPD progression is discussed. These cascading events can lead to neuronal deficits, altered glial cell function, and subsequent cognitive dysfunction. Furthermore, we provide a comprehensive overview of potential medications for treating COPD and its associated cognitive deficits, with a specific focus on anti-inflammatory and antioxidant therapies. This compilation serves as a pivotal foundation for the prevention and management of cognitive dysfunction in COPD.

Keywords: COPD-related neurocognitive disorders (COPD-NCDs); Chronic obstructive pulmonary disease (COPD); Inflammation; Lung-brain axis; Neurocognitive disorders; Oxidative stress..

Figure 1

The lung-brain axis: possible links between COPD and neurological dysfunction. The lung-brain axis is believed to operate bidirectionally and this intricate interplay is facilitated by a complex network involving neuronal, inflammatory, immune, and neuroendocrine signaling pathways (HPA axis). (Created with Biorender.com).

Figure 2

Possible signaling pathways in inflammatory-oxidative stress mediated neural regeneration. CNS injury induces cytokines to interact with ROS and activation of NMDAR leads to calcium efflux, thereby further contributing to intracellular ROS accumulation through the action of NOX. Intracellular ROS inactivates PTEN and leads to the accumulation of PIP3, which directs Akt to the plasma membrane and promotes Akt activation and neurogenesis. In addition, Akt activates p21, thereby disrupting the interaction between Nrf2 and its inhibitor Keap1 and promoting Nrf2 stabilization for detoxification and neuroprotection against excessive ROS action. RTK are up-regulated in response to CNS injury and activate ERK1/2 signaling pathway upon binding to BDNF. All of the above events promote neurogenesis, neuroprotection and synaptic maturation. Finally, ROS induces JNK p38 MAPK, whose synergistic action is essential for debris removal and axonal regeneration. However, high levels of oxidative stress can trigger peroxidation and the formation of 4-HNE lipids, which may adversely affect nerve regeneration. (BDNF - brain-derived neurotrophic factor; ERK1/2 - extracellular signal-regulated protein kinase; 4-HNE - 4-hydroxy-2-nonenal; JNK - c-jun N-terminal kinase; MAPK - mitogen-activated protein kinases; NMDAR - N-methyl-d-aspartate receptor; NOX - NADPH oxidase; Nrf2 - nuclear factor erythroid 2 like 2; PI3K - phosphatidylinositol 3-kinase; PIP2 - phosphatidylinositol (4,5)-bisphosphate; PIP3 - phosphatidylinositol 3,4,5-trisphosphate; PTEN - phosphatase and tensin homolog; RTK - receptor tyrosine kinase) (Created with Biorender.com).

Figure 3

COPD-NCDs may cause altered glial cell function, BBB permeability, and neuronal dysfunction. Bidirectional communication between astrocytes and microglia regulates their responses during CNS inflammation. Upon activation, microglia and astrocytes release neurotoxic NO, glutamate, or downregulate extracellular neurotransmitter uptake, respectively, ultimately leading to neuronal and oligodendrocyte death. Microglia and astrocytes also control oligodendrocyte recruitment by secreting a variety of cytokines. Activated microglia can be polarized into M1/M2 phenotypes under different conditions. Protrusions of M1-type microglia become larger in diameter and present an amoebic state, which have neuroinflammatory effects, while M2-type microglia have significantly more branching and longitudinally extended protrusions, executing an anti-inflammatory effect and having a neuroprotective function. Interactions of activated microglia with astrocytes and endothelial cells increase BBB permeability, whereas bidirectional communication between astrocytes and peripheral immune cells enhances CNS inflammation and leads to disease progression (Created with Biorender.com).