title: Effects of ambrisentan in a patient affected by combined pulmonary fibrosis and emphysema and by severe pulmonary hypertension: clinical, functional, and biomolecular findings.
abstract: Combined pulmonary fibrosis and emphysema (CPFE) is a computed tomography (CT)-defined syndrome of combined pulmonary fibrosis and emphysema, characterized by subnormal spirometry, impairment of gas exchange, and high prevalence of pulmonary hypertension. Although endothelin-1 (ET-1) plays an important role in the development of lung fibrosis as well as in pulmonary hypertension, no ET-1-targeted therapy is currently recommended. Here we report a case of CPFE successfully treated with ambrisentan, an endothelin-A receptor antagonist, and also discuss the biologic mechanisms underlying the observed therapeutic effects. A 79-year-old man with chronic obstructive pulmonary disease (COPD) was referred to our respiratory unit as an outpatient for dyspnea. Clinical, radiologic, and laboratory findings suggested a diagnosis of chronic hypoxemic, type 1 respiratory failure, due to combined pulmonary fibrosis and emphysema, complicated by severe, precapillary pulmonary hypertension. Pharmacologic treatment with ambrisentan induced an initial improvement in clinical symptoms that proved to be very relevant 9 months later. In order to investigate the biologic mechanisms underlying the clinical effects of ambrisentan, we performed an "in vitro" study on primary cultures of fibrotic human lung fibroblasts, as well as on human umbilical vein endothelial cells, incubated for 24 and 48 h with ET-1, in the absence or presence of an overnight treatment with ambrisentan. ET-1 significantly increased cell proliferation and mitogen-activated protein kinase activation (P < 0.01). These effects were significantly (P < 0.01) inhibited by ambrisentan in both cell cultures. In conclusion, we hypothesize that the clinical benefits induced by ambrisentan in this patient with CPFE can be attributed to its vasodilator and anti-proliferative actions, exerted on pulmonary the vascular bed and lung fibroblasts.
authors.affiliation: Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy.
authors.forename: Fernando
authors.initials: F
authors.lastname: Roccia
authors.forename: Benedetta
authors.initials: B
authors.lastname: Campolo
authors.forename: Luca
authors.initials: L
authors.lastname: Gallelli
authors.forename: Carmen
authors.initials: C
authors.lastname: Spaccarotella
authors.forename: Annalisa
authors.initials: A
authors.lastname: Mongiardo
authors.forename: Daniela
authors.initials: D
authors.lastname: Falcone
authors.forename: Rocco
authors.initials: R
authors.lastname: Savino
authors.forename: Girolamo
authors.initials: G
authors.lastname: Pelaia
authors.forename: Ciro
authors.initials: C
authors.lastname: Indolfi
authors.forename: Rosario
authors.initials: R
authors.lastname: Maselli
mesh_terms: D000368:Aged; D004646:Emphysema / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1 / Q000008:administration & dosage / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D006976:Hypertension, Pulmonary / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D010666:Phenylpropionates / Q000494:pharmacology / Q000627:therapeutic use*; D029424:Pulmonary Disease, Chronic Obstructive / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology; D011658:Pulmonary Fibrosis / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D011724:Pyridazines / Q000494:pharmacology / Q000627:therapeutic use*; D012720:Severity of Illness Index; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome
chemical_list: D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D010666:Phenylpropionates; D011724:Pyridazines; C467894:ambrisentan