cAMP-PDE signaling in COPD: Review of cellular, molecular and clinical features

Abstract

Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death among non-contagious diseases in the world. PDE inhibitors are among current medicines prescribed for COPD treatment of which, PDE-4 family is the predominant PDE isoform involved in hydrolyzing cyclic adenosine monophosphate (cAMP) that regulates the inflammatory responses in neutrophils, lymphocytes, macrophages and epithelial cells The aim of this study is to investigate the cellular and molecular mechanisms of cAMP-PDE signaling, as an important pathway in the treatment management of patients with COPD. In this review, a comprehensive literature review was performed about the effect of PDEs in COPD. Generally, PDEs are overexpressed in COPD patients, resulting in cAMP inactivation and decreased cAMP hydrolysis from AMP. At normal amounts, cAMP is one of the essential agents in regulating metabolism and suppressing inflammatory responses. Low amount of cAMP lead to activation of downstream inflammatory signaling pathways. PDE4 and PDE7 mRNA transcript levels were not altered in polymorphonuclear leukocytes and CD8 lymphocytes originating from the peripheral venous blood of stable COPD subjects compared to healthy controls. Therefore, cAMP-PDE signaling pathway is one of the most important signaling pathways involved in COPD. By examining the effects of different drugs in this signaling pathway critical steps can be taken in the treatment of this disease.

Keywords: COPD Therapy; Phosphodiesterase inhibitors; cAMP signaling.

Fig. 1

A) The E class of G Protein-Coupled Receptors (GPCRs) is tightly regulated by cAMP. PDE causes the deactivation of AMP and the conversion of cAMP to AMP. In response to a wide range of stimuli, cAMP is universally produced and controlled, influencing a wide range of downstream biochemical and signaling pathways, including PKA, AMPK, and Epac signaling modules, which modulates inflammatory responses. B) Increased cAMP levels trigger PKA, which then inhibits the pro-inflammatory effector RhoA (NF-κB pathway activator). In addition, endothelial dysfunction in individuals with COPD is related to the GTP-RhoA family (ROCK). C) Epac is a cAMP-sensitive guanine exchange factor (GEF) that connects members of the Ras superfamily including Rho, Rac, and Ras at the molecular level. Pro-inflammatory interleukins are less activated when Epac1 is activated by cAMP by altering many signaling pathways, such as PI3k/Akt, ERK, phospholipase D, and NF-κB. D) AMPK (AMP-activated protein kinase) interacts with cAMP- stimulated PKA to restrict the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway and reduce inflammation. The oxidant-antioxidant balance is related to AMPK's anti-inflammatory properties, and AMPK activation increases Nrf2 expression. Furthermore, AMPK regulates protein synthesis by activating tuberous sclerosis complex 2 (TSC2), suppressing mTORC1, and regulating autophagy via ULK1 (UNC51-like kinase 1). STAT3 may be blocked by both cAMP and AMPK triggered by cAMP, which inhibits the downstream inflammatory pathways. E) The effect of symbiosis and dysbiosis in the downstream signaling pathways and their effect on cAMP turn-over.

Fig. 2

PDE inhibitor drugs prevent the conversion of cAMP to AMP, thereby activating cAMP. Activation of PKA is one of the downstream pathways of cAMP, which can inactivate and reverse many inflammatory pathways involved in COPD. Suppressing the pro-inflammatory factor RhoA as a result of inhibiting the inflammatory pathways of p38 MAPK and finally the transcription factor NFKB, leads to inhibiting the release of many inflammatory factors such as IL-1B, IL-18, IL-8, IL-6, TNF-α, MMP2, and MMP9. PKA also leads to phosphorylation and inhibition of JAK-STAT3 and mTORC1 through AMPK, which can prevent the progress of inflammation by cytokines such as IL-22, IL-17 and IL-22. The activation of AMPK can also lead to the activation of FOXO family transcription factors, which will result in the inhibition of NFKB and pro-inflammatory factors. Finally, the blocking of the HIF1 pathway and the inactivation of IL17 leads to a decrease in the concentration of MMPs, preventing tissue damage due to the overactivation of the immune system.

Fig. 3

Epac1 is activated by the inhibition of PDEs and as a result the activation of cAMP and leads to the inhibition of the PI3K/Akt pathway, which as a result of this inhibition and dephosphorylation of FOXO3 (activation) blocks NF-KB and other inflammatory factors caused by it. PTEN is a negative regulator of PI3K, converting phosphatidylinositol-3,4,5-phosphate (PIP3) to phosphatidyl-4,5-phosphate (PIP2), which results in the production of many pro-inflammatory factors such as IL6, IL1, IL-8 and TNFA are inhibited and inflammation is prevented.

Fig. 4

The association between cAMP, dysbiosis, and symbiosis. cAMP has a central role in the homeostasis between the immune system and the human microbiome in the body. In the physiological condition, the symbiotic microbiome produces short-chain fatty acids that lead to the inhibition of cAMP-CRP and thus increase the level of cAMP. cAMP activates T-reg inhibitory responses resulting in homeostasis. On the contrary, microbiome dysbiosis decreases cAMP levels and leads to local or systemic inflammation.

Fig. 5

Some important examples of bacterial mechanisms to increase host cell levels of cAMP. Pathogenic bacteria directly or indirectly (through producing some metabolites that impact cAMP) induce cAMP to increase in the host cells. For example, Bordetella pertussis and Vibrio cholerae produce ADP-ribosylating toxins, and Bartonella produces BepA metabolite to produce cAMP. Some bacteria produce class III PDE enzymes that degrade cAMP. For example, Mycobacterium tuberculosis produces Rv0805, and E coli, Vibrio vulnificus, and Pseudomonas aeruginosa produce CpdA as a major class III PDE that hydrolyzes cAMP. Using CpdA PDE, Pseudomonas aeruginosa can produce adenylate cyclase to increase cAMP levels in the cells, and Mycobacterium tuberculosis can produce and inject directly cAMP into the host cells.