Pathway Reconstruction of Airway Remodeling in Chronic Lung Diseases: A Systems Biology Approach

Abstract

Airway remodeling is a pathophysiologic process at the clinical, cellular, and molecular level relating to chronic obstructive airway diseases such as chronic obstructive pulmonary disease (COPD), asthma and mustard lung. These diseases are associated with the dysregulation of multiple molecular pathways in the airway cells. Little progress has so far been made in discovering the molecular causes of complex disease in a holistic systems manner. Therefore, pathway and network reconstruction is an essential part of a systems biology approach to solve this challenging problem. In this paper, multiple data sources were used to construct the molecular process of airway remodeling pathway in mustard lung as a model of airway disease. We first compiled a master list of genes that change with airway remodeling in the mustard lung disease and then reconstructed the pathway by generating and merging the protein-protein interaction and the gene regulatory networks. Experimental observations and literature mining were used to identify and validate the master list. The outcome of this paper can provide valuable information about closely related chronic obstructive airway diseases which are of great importance for biologists and their future research. Reconstructing the airway remodeling interactome provides a starting point and reference for the future experimental study of mustard lung, and further analysis and development of these maps will be critical to understanding airway diseases in patients.

Long non‑coding RNA TUG1 accelerates abnormal growth of airway smooth muscle cells in asthma by targeting the miR‑138‑5p/E2F3 axis

“…It has been documented that airway remodelling accelerates structural changes to the airway in patients with asthma, leading to irreversible or partially irreversible airflow obstruction (24).…”

Integration of Airway Inflammation and Remodeling Mechanisms Specific to Eosinophilic Asthma Through Differential Co-Expression of Genes in Bronchial Brush Biopsy Samples

“…Furthermore, Sp1 has an established role in asthma pathogenesis as a transcription factor for (1) lipooxygenase ALOX5 35 , which promoter region's polymorphism affects asthma control, and (2) vascular endothelial growth factor (VEGF), hypersecreted from ASM in asthma and contributing to remodeling. Of note, both ATP1B1 and RECK are implied to take part in airway remodeling in mustard lung 36 , adding to evidence of Sp1-regulated genes in airway pathology. ATP1B1 was one of the genes included in transcriptomic cluster TAC3 of patients with moderate to high sputum eosinophilia in the U-BIOPRED cohort of Th2-dependent asthma 37 , with our study being the second to indicate the link.…”

Systems medicine: evolution of systems biology from bench to bedside

“…The mechanistic underpinnings of lung injury responses have also been addressed using a combination of network biology strategies in order to understand better the pathways resulting in airway remodeling. In a unique experimental design, airway biopsy samples from lungs of patients exposed remotely to sulfur mustard or unexposed controls were subjected to microarray gene expression analysis and combined with genes corresponding to biological factors linked to airway remodeling identified from curated literature searches . From these datasets, PPI and gene regulatory networks could be synthesized, which were ultimately merged to create functional modules.…”

“…In a unique experimental design, airway biopsy samples from lungs of patients exposed remotely to sulfur mustard or unexposed controls were subjected to microarray gene expression analysis and combined with genes corresponding to biological factors linked to airway remodeling identified from curated literature searches. 79 From these datasets, PPI and gene regulatory networks could be synthesized, which were ultimately merged to create functional modules. In that study, matrix remodeling proteins, particularly matrix metalloproteinase (MMP)-9, were centrally located and well connected within the network.…”