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.