Bronchodilation induced by PGE₂ is impaired in Group III pulmonary hypertension

Abstract

Background and purpose: In patients with pulmonary hypertension (PH) associated with lung disease and/or hypoxia (Group III), a reduction of pulmonary vascular tone and tissue hypoxia are considered therapeutically beneficial. Prostaglandin (PG) E2 and PGI2 induce potent relaxation of human bronchi from non-PH (control) patients via EP4 and IP receptors, respectively. However, the effects of PGE2/PGI2 and their mimetics on human bronchi from PH-patients are unknown. Our aim was to compare the relaxant effects of several PGI2mimetics approved for treating PH-Group I with several PGE2-mimetics in bronchial preparations derived from PH-Group III and control patients. Experimental approach: Using an organ bath system, the tone of bronchial muscle was investigated in tissue from either control or PH-Group III patients. Expression of prostanoid receptors were analyzed by Western blot and real-time PCR and endogenous PGE2, PGI2 and cAMP levels were determined by ELISA.

International Union of Basic and Clinical Pharmacology. CIX. Differences and Similarities between Human and Rodent Prostaglandin E2Receptors (EP1–4) and Prostacyclin Receptor (IP): Specific Roles in Pathophysiologic Conditions

“…EP4-receptor expression was not modified in pulmonary arteries or lungs derived from chronically hypoxic PH rats or monocrotaline-treated rats and patients with PAH; this was demonstrated by real-time PCR, Western blot, and immunohistochemical studies (Lai et al, 2008;Li et al, 2018;Fan et al, 2019a). However, our recent study demonstrated that there is a decrease of EP4-receptor expression in bronchi derived from PH group-III patients by Western blot and real-time PCR techniques (Ozen et al, 2020b). Another recent study performed on hypoxia-induced PH rats revealed that the beneficial effect of beraprost (PGI 2 analog) is mediated via the EP4 receptor-related pathway (Tian et al, 2019).…”

“…In a similar way, in a rat model of PH, iloprost treatment was effective at reducing bronchial hyper-reactivity induced by methacholine (Habre et al, 2011). Although the majority of effects of PGI 2 analogs on bronchial muscle tone have been attributed to the IP receptor, EP4 and DP1 receptors may also contribute to the actions of treprostinil, particularly at higher analog concentrations (Ozen et al, 2020b).…”

“…The effects of PGE 2 on human bronchial SMC are well documented and globally considered as being “bronchoprotective.” Bronchoprotection is explained by several direct and indirect mechanisms. Low (<1 µM) concentrations of PGE 2 attenuated histamine- or anti-IgE–induced contraction in small (<1 mm in diameter) and larger human bronchi ex vivo through an EP4 receptor–dependent effect ( Buckley et al, 2011 ; Benyahia et al, 2012 ; Safholm et al, 2015 ; Ozen et al, 2020b ). This EP4 receptor–mediated relaxation was related to a direct effect on the human bronchial SMC.…”

“…Most of our knowledge about PH and the development of pharmacological/therapeutic strategies has focused on PH group-I (PAH). More studies in PH patients from other groups are necessary; the recently published work with human bronchi (Ozen et al, 2020b) suggests that inhaled PGI 2 analogs may also have a promising therapeutic effect in PH group-III, which is one of the most common and lethal forms of PH. In PH group-III, PH is secondary to respiratory diseases, such as COPD, so in this case, inhaled PGI 2 could have a dual effect by decreasing airway resistance, thus supplying more of this vasorelaxant drug and oxygen to pulmonary arteries.…”

“…Ex vivo studies performed on preparations derived from lung or pulmonary arteries have consistently shown not only a reduction of PGI 2 synthesis but also of the IP-receptor expression in both patients with PH and rats treated with monocrotaline and hypoxia that develop PH ( Lai et al, 2008 ; Falcetti et al, 2010 ; Jiang et al, 2013 ; Li et al, 2018 ; Fan et al, 2019a ; Clapp et al, 2020 ; Ozen et al, 2020a , b ). The impairment of the PGI 2 pathway in PH lungs underlies the rationale for why the administration of vasodilators, such as PGI 2 or mimetics (IP agonists), are beneficial in the treatment of PH patients awaiting lung transplantation.…”