Altered Hypoxic–Adenosine Axis and Metabolism in Group III Pulmonary Hypertension

Abstract

Group III pulmonary hypertension (PH) is a highly prevalent and deadly lung disorder with limited treatment options other than transplantation. Group III PH affects patients with ongoing chronic lung injury, such as idiopathic pulmonary fibrosis (IPF). Between 30 and 40% of patients with IPF are diagnosed with PH. The diagnosis of PH has devastating consequences to these patients, leading to increased morbidity and mortality, yet the molecular mechanisms involved in the development of PH in patients with chronic lung disease remain elusive. Our hypothesis was that the hypoxic-adenosinergic system is enhanced in patients with group III PH compared with patients with IPF with no PH. Explanted lung tissue was analyzed for markers of the hypoxic-adenosine axis, including expression levels of hypoxiainducible factor (HIF)-1A, adenosine A2B receptor, CD73, and equilibrative nucleotide transporter-1. In addition, we assessed whether altered mitochondrial metabolism was present in these samples. Increased expression of HIF-1A was observed in tissues from patients with group III PH. These changes were consistent with increased evidence of adenosine accumulation in group III PH. A novel observation of our study was of evidence suggesting altered mitochondrial metabolism in lung tissue from group III PH leading to increased succinate levels that are able to further stabilize HIF-1A. Our data demonstrate that the hypoxic-adenosine axis is up-regulated in group III PH and that subsequent succinate accumulation may play a part in the development of group III PH.Keywords: group III pulmonary hypertension; adenosine A2B receptor; idiopathic pulmonary fibrosis; succinate; hypoxiainducible factor-1A Clinical RelevanceThis study shows that alterations in metabolism lead to enhanced activation of the hypoxic-adenosine axis that contribute to the development of pulmonary hypertension associated with idiopathic pulmonary fibrosis. These findings suggest that targeting elements of the hypoxic-adenosine axis could be used therapeutically for group III pulmonary hypertension, for which currently no effective strategies exist.

Inhibition of hyaluronan synthesis attenuates pulmonary hypertension associated with lung fibrosis

“…Taken together, these studies demonstrate that hyaluronan synthesis is up‐regulated, perhaps as a protective response, but that the higher levels of hyaluronidases and oxidative stress lead to degradation of hyaluronan to pathogenic factors. Although the mechanisms that lead to elevated expression of HAS and HYALs are not the focus of this study, we anticipate that activation of the adenosine A 2B receptor to modulate this process, consistent with the notion of elevated adenosinergic‐hypoxic axis in PH associated with IPF (Garcia‐Morales et al, ) and the role of adenosine in modulating hyaluronan synthesis associated with chronic obstructive pulmonary disease (Karmouty‐Quintana et al, ). It is well known that higher molecular fragments of hyaluronan are beneficial (Aytekin et al, ).…”

“…The demographic details of the study population are summarized in Table . De‐identified lung explant tissue from patients with IPF and corresponding de‐identified clinical parameters were obtained from the Methodist Hospital (Houston, TX) as described previously (Garcia‐Morales et al, ). IPF was diagnosed by board‐certified pulmonologists upon admittance for lung transplantation at the Houston Methodist Hospital using published guidelines (Raghu et al, ).…”

“…As described previously (Garcia‐Morales et al, ), tissue was collected at the time of lung explantation and processed on site within 20 min. The lobes were identified from each lung explant, and for each lobe, the centre was identified, taking the airway as a reference point.…”

Glutamine metabolism drives succinate accumulation in plasma and the lung during hemorrhagic shock

“…(8, 21) Succinate accumulation has also been recently implicated in pulmonary hypertension both in in vitro and in vivo models. (35, 36) In our analysis, total succinate levels are elevated in lung tissue, corroborating succinate as a potential inflammatory mediator capable of priming the lung for a “second-hit” after injury. (1) (Figure 4a) Labeling in succinate (M+4) in lung tissue also confirms that succinate accumulated in the lung derives from glutamine.…”

Adenosine Receptors As Drug Targets for Treatment of Pulmonary Arterial Hypertension

“…The authors stated that, under acute conditions, hyperactivation of the A 2B receptor by adenosine is protective and leads to lung tissue repair. In humans with lung fibrosis, however, sustained activation of the receptor is deleterious and contributes to development of pulmonary vascular remodeling and PH ( Garcia-Morales et al, 2016 ).…”