Eur Respir J 2010; 35: 730–734 DOI: 10.1183/09031936.00097109 CopyrightßERS Journals Ltd 2010 PERSPECTIVE Asthma and pulmonary arterial hypertension: do they share a key mechanism of pathogenesis? S.I. Said*,#, S.A. Hamidi*,# and L. Gonzalez Bosc" ABSTRACT: Although largely distinct and seemingly unrelated, asthma and pulmonary arterial AFFILIATIONS hypertension (PAH) have important pathological features in common, including inflammation, *Pulmonary and Critical Care Medicine, Stony Brook University, smooth muscle contraction and remodelling. Stony Brook, NY, We hypothesised that these common features could be explained by one shared mechanism of #Dept of Veterans Affairs Medical pathogenesis: activation of the transcription factor NFAT (nuclear factor of activated T-cells). If Center, Northport, NY, and " this concept is validated, it could lead to the introduction of novel therapeutic strategies against Dept of Cell Biology and Physiology, University of New both lung disorders. Mexico, Albuquerque, NM, USA. In several experimental models, airway remodelling is accompanied by remodelling of smaller pulmonary arteries, validating the hypothesis of their similar pathogenesis. In addition, lungs of CORRESPONDENCE vasoactive intestinal peptide (VIP) knockout mice express airway hyperresponsiveness with S.I. Said Pulmonary and Critical Care airway inflammation and PAH with vascular remodelling, with both sets of pathological findings Medicine being reversible with VIP treatment. Preliminary data suggest that absence of the VIP gene leads Stony Brook University; T-17-040 to activation of the calcineurin–NFAT pathway, and that VIP is probably a physiological inhibitor of Stony Brook this pathway. 11794 NY USA Enough evidence exists to support the views that asthma and PAH share important pathological E-mail: [email protected] features, probably related to NFAT activation, and that VIP may be a physiological modulator of this mechanism. Received: June 19 2009 Accepted after revision: KEYWORDS: Asthma, pulmonary hypertension, remodelling, transcription factor Oct 08 2009 sthma, a disease of the airways, and the question: can a single basic mechanism be at pulmonary arterial hypertension (PAH), the root of the major features of asthma? Herein, A a disease of the pulmonary circulation, we review evidence for the existence of such a have markedly different clinical presentations. mechanism, one that might also help explain the On closer examination, however, the two dis- basic pathological processes of PAH. eases can be shown to share several key pathological features. COMMON PATHOLOGICAL FEATURES IN ASTHMA AND PAH Asthma is a multifaceted disease characterised by Both asthma and PAH exhibit three major patho- airway hyperresponsiveness (AHR), airway logical features: inflammation, smooth muscle inflammation and varying degrees of smooth constriction, and smooth muscle cell proliferation. muscle cell proliferation termed airway remodel- ling [1–7]. Research has often focused on one or Inflammation has long been acknowledged as a another of the component elements of the cardinal feature of the asthmatic response [1, 7, 8], asthmatic response, and corresponding therapeu- and has been gaining increasing recognition as a tic initiatives have been proposed with varying significant component of clinical and experimental degrees of success. However, the disease con- PAH phenotypes [9]. In both diseases there is tinues to present challenges to physicians and increased resistance in, and narrowing of, airways investigators alike. The very complexity of the and pulmonary arteries, respectively, due to European Respiratory Journal disease has stimulated the search for more airway and pulmonary vasoconstriction [10], Print ISSN 0903-1936 comprehensive answers, and even prompted smooth muscle constriction, and thickening of Online ISSN 1399-3003 730 VOLUME 35 NUMBER 4 EUROPEAN RESPIRATORY JOURNAL S.I. SAID ET AL. PERSPECTIVE the walls caused by smooth muscle and other cell proliferation lacking the vasoactive intestinal peptide (VIP) gene are associated known as remodelling. Muscularisation and remodelling of with, and attributable to, NFAT activation. smaller pulmonary arteries are essential pathological lesions in PAH [11, 12]. Asthmatic airway inflammation causes tissue NFAT ACTIVATION IN THE PATHOGENESIS OF PAH injury and related structural changes that may lead to airway NFAT activation has been identified in experimental models of remodelling, as described in humans and in experimental PAH, and in one clinical form of the disease, idiopathic PAH models in mice and rats [13–20]. Remodelling includes an (IPAH). DE FRUTOS et al. [30] presented evidence that NFATc3 increase in airway wall thickness, fibrosis, smooth muscle mass activation mediates chronic hypoxia-induced pulmonary vas- and vascularity, as well as abnormalities in extracellular matrix cular hypertrophy and remodelling in mice, with a-actin composition [17, 21]. Recent reviews have addressed the upregulation. KOULMANN, et al. [31] demonstrated the critical molecular mechanisms, consequences and significance of air- role of calcineurin activation in the production of hypoxia- way remodelling, along with its lack of responsiveness to induced PAH and right ventricular hypertrophy in rats. Both current pharmacological therapy [5–7, 22–25]. pathological findings were fully prevented by treatment with calcineurin inhibitor cyclosporin A. NFATc2 activation has been These shared pathological features between asthma and PAH demonstrated in small- and medium-sized pulmonary arteries are unlikely to be strictly coincidental. Rather, they probably of rats with monocrotaline-induced PAH [32]. Cyclosporin A reflect a single underlying mechanism that is common to both reversed PAH in vivo and reversed several features of the PAH diseases. Compelling evidence points to one particular phenotype of pulmonary arterial smooth muscle cells transcription factor as playing a key role in this mechanism. + (PASMCs), including decreased voltage gated K (KV) current CALCINEURIN–NUCLEAR FACTOR OF ACTIVATED T- and KV1.5 expression [32]. Similarly, in IPAH patients, NFATc2 CELLS SIGNALLING was activated in PASMCs, lung and T-lymphocytes. Inhibition of NFATc2 decreased PASMC proliferation and increased Transcription factors of the NFAT (nuclear factor of activated apoptosis in vitro [32]. Selective inhibition of calcineurin– T-cells) family are master regulators of immune responses, as NFAT signalling in the lungs of VIP-/- mice attenuated the well as of gene expression in a host of tissues and organs, pathological changes of PAH (as well as of asthma) in these including smooth muscle (fig. 1). Four of the NFAT proteins mice, and PASMCs showed predominant nuclear localisation, (NFATc1, NFATc2, NFATc3 and NFATc4) are normally i.e. activation of NFATc (unpublished data). cytoplasmic, i.e. inactive. However, upon dephosphorylation 2+ by the Ca -responsive phosphatase calcineurin, the proteins COMBINED FEATURES OF ASTHMA AND PAH IN THE are activated and translocated to the nucleus. Activated NFAT SAME EXPERIMENTAL MODELS exerts its multiple regulatory actions by forming co-operative If the same molecular mechanism underlies the pathogenesis complexes with other transcription factors, including the of both asthma and PAH, we might expect that, at least in some activator protein-1 family of proteins [26]. instances, both airway and vascular pathology might be THE ROLE OF NFAT ACTIVATION IN THE expressed concomitantly in the same lung. PATHOGENESIS OF INFLAMMATORY AND We first observed this combined pathology in mice lacking the IMMUNOLOGICAL DISORDERS VIP gene. As reported earlier, such mice simultaneously NFAT proteins are expressed on T-cells and other classes of express AHR with airway inflammation, together with PAH, immune system cells, such as B-cells, mast cells, eosinophils and pulmonary vascular remodelling and perivascular inflamma- natural killer cells. NFAT proteins are activated by stimulation tion (fig. 2). Treatment of the mice with VIP reversed both sets 2+ of Gq-coupled receptors coupled to Ca mobilisation, such as of phenotypic changes, confirming that they result from the antigen receptors on T- and B-cells, and receptors on other cells. absence of the VIP gene [33, 34]. NFAT transcription factors are key regulators of inducible gene transcription during the immune response. NFAT activation can In a model of Th2 immune response, C57BL/6 mice developed also promote smooth muscle cell proliferation and, thus, severe pulmonary arterial remodelling after immunisation and contribute to the proliferative reaction in airway remodelling. prolonged intermittent exposure to intranasal Aspergillus fumigatus [35]. Despite the vascular remodelling there was no EVIDENCE LINKING NFAT ACTIVATION DIRECTLY TO significant increase in pulmonary arterial pressure. This ASTHMA PATHOGENESIS unexplained discrepancy raises the possibility that some In a model of allergic airway inflammation, transgenic mice asthmatics, such as these mice, might have unrecognised expressing dominant-negative NFAT mutant exclusively in T- pulmonary vascular remodelling. cells showed reduced antigen-specific T-helper (Th)2 antibody Female BALB/C mice that were sensitised and repeatedly levels and interleukin (IL)-4 production by CD4+ T-cells. challenged with ovalbumin developed remodelling of bronchi, Furthermore, accumulation of eosinophils in bronchoalveolar as well as inflammation and remodelling of pulmonary lavage fluid was