Please cite this article in press as: E.A. Hamed, et al., Molecular mechanisms underlying fibrosis and elastin destruction in childhood interstitial lung diseases, Pathophysiology (2016), http://dx.doi.org/10.1016/j.pathophys.2016.09.001 ARTICLE IN PRESS G Model PATPHY-880; No. of Pages 9 Pathophysiology xxx (2016) xxx–xxx Contents lists available at ScienceDirect Pathophysiology journal homepage: www.elsevier.com/locate/pathophys Molecular mechanisms underlying fibrosis and elastin destruction in childhood interstitial lung diseases Enas A. Hamed (M.D.) a,∗ , Mostafa M. El-Saied a , Khaled Saad a , Hazem Abu-Zeid Yousef b , Amany O. Mohamed c , Dina Sabry d a Department of Pediatrics, Faculty of Medicine, Assiut University, Assiut, Egypt b Department of Radiology, Faculty of Medicine, Assiut University, Assiut, Egypt c Department of Medical Biochemistry, Faculty of Medicine, Assiut, University, Assiut, Egypt d Department of Medical Biochemistry, Faculty of Medicine, Cairo University, Cairo, Egypt a r t i c l e i n f o Article history: Received 27 June 2016 Received in revised form 22 August 2016 Accepted 18 September 2016 Available online xxx Keywords: Connective tissue growth factor (CCN2) Interstitial lung disease of children Long non-coding RNAs Transforming growth factor (TGF)-1 Urinary desmosine (UDes) a b s t r a c t Objective: This study aimed to evaluate fibrosis and elastin destruction in childhood interstitial lung disease (chILD) patients. Methods: Sixty patients and twenty healthy children were recruited. On admission, evaluation of chILD severity was made using Fan chILD score. Participants provided urine and blood samples. Plasma levels of transforming growth factor (TGF)- 1 , connective tissue growth factor (CCN2), soluble factor related apoptosis (sFas) and long non-coding RNAs and urinary levels of desmosine/urinary creatinine (UDes/UCr) were measured. Results: In patients, clinical findings were crackles (100.00%), tachypnea (65.00%), cardiomegaly (45.00%), digital clubbing (43.30%), cough (33.00%), cyanosis (26.70%), hepatomegaly (28.30%) and wheezes (23.30%). Categorizing of the patients with Fan chILD clinical score revealed that most patients 33.30% scored (3, symptomatic with abnormal saturation/cyanosis during exercise) then 28.30% scored (5, symp- tomatic with clinical and echocardiographic features of pulmonary hypertension), 18.30% scored (2, symptomatic with normal room air saturations), 15.00% scored (1, asymptomatic) and 5.00% scored (4, symptomatic with abnormal room air saturation/cyanosis at rest). TGF- 1 , CCN2, sFas, lncrRNA- 2700086A05Rik relative gene expression and UDes/UCr levels were higher in patients than controls (P = 0.002, P = 0.001, P = 0.001, P = 0.001, P = 0.001, respectively). In patients, significant positive correla- tions were found between TGF- 1 and CCN2, sFas, UDes/UCr; between CCN2 and both sFas and UDes/UCr; between UDes/UCr and sFas. Morbidity and mortality rates were 46.70% and 10.00%, respectively. Conclusion: Markers of fibrosis (TGF- 1 , sFas, CCN2) and elastin destruction (UDes/UCr) were increased in chILD especially in patients with long disease duration. So blockage of their pathways signals may offer novel therapeutic targets. © 2016 Elsevier B.V. All rights reserved. Abbreviations: ARDS, acute respiratory distress syndrome; AECs, alveolar epithe- lial cells; BMI, body mass index; CXR, chest X-ray; chILD, childhood interstitial lung disease; CPI, chronic pneumonitis of infancy; CCN2, connective tissue growth factor; CT, critical threshold; ECM, extracellular matrix; DIP, desquamative inter- stitial pneumonitis; DAD, diffuse alveolar damage; EMT, epithelial-mesenchymal transition; ERS, European Respiratory Society; HRCT, high-resolution computed tomography; lncRNAs, long non-coding RNAs; LIP, lymphocytic interstitial pneu- monia; NSIP, idiopathic interstitial pneumonias; IPF, interstitial pulmonary fibrosis; OP, organizing pneumonia; PAP, pulmonary alveolar proteinosis; sFas, soluble factor related apoptosis; TGF-1, transforming growth factor-1; UDes/UCr, urinary levels of desmosine/urinary creatinine; UIP, usual interstitial pneumonia. ∗ Corresponding author at: Department of Pediatrics, Faculty of Medicine, Assiut University, Assiut, Egypt. E-mail address: eah3a2010@yahoo.com (E.A. Hamed). 1. Introduction Childhood interstitial lung diseases (chILDs) represent a rare heterogeneous group of clinical entities with diffuse lung involve- ment. These disorders involve the interstitium as well as the distal airspaces that result in restrictive lung physiology and significant impairment of gas exchange. Three studies reported the frequency of chILD in general populations [1–3]. Incidence estimates var- ied from 0.13 cases/100,000 children <17 years of age/year in Germany [3] to 0.36 cases/100,000 in immune–competent children <17 years of age in the United Kingdom and Ireland [1] to 10.8–16.2 cases/100,000 children <15 years of age/year in Denmark [2]. Five hospital–based studies of children [4–8] indicated that between 1.3 http://dx.doi.org/10.1016/j.pathophys.2016.09.001 0928-4680/© 2016 Elsevier B.V. All rights reserved.