Abstract
The extracellular matrix (ECM) is a key regulator of tissue morphogenesis and repair. However, its composition and architecture are not well characterized. Here, we monitor remodeling of the extracellular niche in tissue repair in the bleomycin-induced lung injury mouse model. Mass spectrometry quantified 8,366 proteins from total tissue and bronchoalveolar lavage fluid (BALF) over the course of 8 weeks, surveying tissue composition from the onset of inflammation and fibrosis to its full recovery. Combined analysis of proteome, secretome, and transcriptome highlighted post-transcriptional events during tissue fibrogenesis and defined the composition of airway epithelial lining fluid. To comprehensively characterize the ECM, we developed a quantitative detergent solubility profiling (QDSP) method, which identified Emilin-2 and collagen-XXVIII as novel constituents of the provisional repair matrix. QDSP revealed which secreted proteins interact with the ECM, and showed drastically altered association of morphogens to the insoluble matrix upon injury. Thus, our proteomic systems biology study assigns proteins to tissue compartments and uncovers their dynamic regulation upon lung injury and repair, potentially contributing to the development of anti-fibrotic strategies.
Highlights
The lung is constantly subjected to harmful exposures, such as inhaled toxic substances, particulate matter, autoimmune reactions, and viral or bacterial infections that cause injury to the airway and alveolar epithelium
In a process called fibrogenesis, several mesenchymal cell populations secrete and assemble a specialized provisional extracellular matrix (ECM), which acts as a scaffold and master regulator of developmental programs in concert with extracellular morphogens, such as growth factors, cytokines, and chemokines (Gurtner et al, 2008)
Developmental signaling pathways active in tissue repair, such as the TGF-b, Wnt, Shh, or Bmp pathways, which emanate from secreted morphogens and are regulated by interacting ECM components (Kleinman et al, 2003), are often deregulated in chronic lung diseases, potentially causing persistent pulmonary fibrosis (Fernandez & Eickelberg, 2012)
Summary
The lung is constantly subjected to harmful exposures, such as inhaled toxic substances, particulate matter, autoimmune reactions, and viral or bacterial infections that cause injury to the airway and alveolar epithelium. Bioinformatic analysis of protein domain architecture, together with literature mining, has defined an ECM component list (the “matrisome”) by classifying secreted proteins into structural constituents of the ECM (“core matrisome”) and ECM-interacting proteins (“matrisome-associated”) (Cromar et al, 2012; Naba et al, 2012a,b). Developmental signaling pathways active in tissue repair, such as the TGF-b, Wnt, Shh, or Bmp pathways, which emanate from secreted morphogens and are regulated by interacting ECM components (Kleinman et al, 2003), are often deregulated in chronic lung diseases, potentially causing persistent pulmonary fibrosis (Fernandez & Eickelberg, 2012).
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