Introduction
Heart failure (HF) currently affects 64 million people worldwide with increasing prevalence [1]. Thus, health care expenditures are substantial; and considering our ageing population, they will continue to rise. HF morbidity and mortality are still high despite remarkable advancements in prevention and therapy [2]. Moreover, quality of life remains poor for HF patients [3] as HF causes injury and dysfunction of target organs, including the lung [4-7]. Although this affects primary disease management and outcome, the mechanisms underlying target organ injury in HF remain incompletely understood and hence, safe and efficient treatment strategies are limited. Regarding HF-associated lung complications, progress has been made in understanding the pathophysiology of pulmonary oedema, but other pulmonary complications of HF continue to challenge patients and clinicians alike.
Similar to several chronic lung diseases [8], elevated biomarker levels of inflammation are features of chronic HF. An augmentation in pro-inflammatory cytokines, including tumour necrosis factor alpha (TNF-α) [9], has been demonstrated to play a role during HF progression, suggesting an involvement of inflammation during HF-mediated target organ damage [10]. We previously showed that therapeutically scavenging TNF-α using Etanercept attenuates target organ dysfunction in a mouse model of HF [7]. Therapeutic interventions aimed at limiting TNF-α-mediated inflammation in chronic HF or lung diseases have yielded controversial results [11]. Considering this, we invested in understanding the molecular mechanism by which TNF-α signalling promotes target organ function during experimental HF [12]. Particularly, we showed that elevated TNF-α levels lead to considerable downregulation of the cystic fibrosis transmembrane regulator (CFTR) in the murine vasculature, heart, brain, and lung tissue [5]. The importance of proper CFTR function is appreciated in cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD). Here, CFTR protein dysfunction is common in the airways of affected patients [13]. In contrast to the genetic origin in CF, CFTR dysfunction in COPD is acquired since neutrophil elastase can induce alterations of CFTR expression, which correlate with disease severity [14]. Besides epithelial [15] and smooth muscle cells [5, 6], CFTR expression has been documented in several immune cells [16, 17]. Peripheral blood monocytes isolated from patients heterozygous for the F508del CFTR mutation showed enhanced interleukin (IL)-8 secretion after activation compared to non-CF controls [18]. The latter was corroborated in macrophages isolated from Cftrknockout mice [19], suggesting a hyperinflammatory phenotype. Interestingly, pharmacological CFTR inhibition in macrophages increased secretion of pro-inflammatory cytokines [17], suggesting that acquired CFTR dysfunction (e.g., induced by HF, smoking or neutrophil elastase [14, 20, 21]) may contribute to hyperinflammatory immune responses. Since dysregulation of inflammation represents a hallmark of multiorgan manifestations of many diseases, including HF, we tested the hypothesis that murine HF associates with pulmonary CFTR dysfunction and concurrent tissue inflammation, which is correctable by CFTR targeting therapy.