The UIP/IPF fibroblastic focus is a collagen biosynthesis factory embedded in a distinct extracellular matrix
Jeremy A. Herrera, Lewis Dingle, M. Angeles Montero, Rajamiyer V. Venkateswaran, John F. Blaikley, Craig Lawless, Martin A. Schwartz
Jeremy A. Herrera, Lewis Dingle, M. Angeles Montero, Rajamiyer V. Venkateswaran, John F. Blaikley, Craig Lawless, Martin A. Schwartz
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Research Article Pulmonology

The UIP/IPF fibroblastic focus is a collagen biosynthesis factory embedded in a distinct extracellular matrix

Abstract

Usual interstitial pneumonia (UIP) is a histological pattern characteristic of idiopathic pulmonary fibrosis (IPF). The UIP pattern is patchy with histologically normal lung adjacent to dense fibrotic tissue. At this interface, fibroblastic foci (FF) are present and are sites where myofibroblasts and extracellular matrix (ECM) accumulate. Utilizing laser capture microdissection-coupled mass spectrometry, we interrogated the FF, adjacent mature scar, and adjacent alveoli in 6 fibrotic (UIP/IPF) specimens plus 6 nonfibrotic alveolar specimens as controls. The data were subjected to qualitative and quantitative analysis and histologically validated. We found that the fibrotic alveoli protein signature is defined by immune deregulation as the strongest category. The fibrotic mature scar classified as end-stage fibrosis whereas the FF contained an overabundance of a distinctive ECM compared with the nonfibrotic control. Furthermore, FF were positive for both TGFB1 and TGFB3, whereas the aberrant basaloid cell lining of FF was predominantly positive for TGFB2. In conclusion, spatial proteomics demonstrated distinct protein compositions in the histologically defined regions of UIP/IPF tissue. These data revealed that FF are the main site of collagen biosynthesis and that the adjacent alveoli are abnormal. This essential information will inform future mechanistic studies on fibrosis progression.

Authors

Jeremy A. Herrera, Lewis Dingle, M. Angeles Montero, Rajamiyer V. Venkateswaran, John F. Blaikley, Craig Lawless, Martin A. Schwartz

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Figure 9

The FF.

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The FF. The lesion of UIP/IPF is termed the FF and can be envisioned as ...
The lesion of UIP/IPF is termed the FF and can be envisioned as the invasive front. The FF progresses toward adjacent alveoli, leaving behind a dense mature scar tissue. Herein, we provide a list of proteins (ECM and cell surface) that are abundantly and significantly overexpressed per region. We define the FF as a collagen biosynthesis factory that expresses both TGFB1 and TGFB3, while embedded in a unique ECM, a switch from normal. Adjacent to the FF, the mature scar is characterized as end-stage fibrosis, which is stiffer than the rest of the fibrotic tissue. The alveoli adjacent to the FF accumulate macrophages and are defined by immune dysregulation. The epithelial lining along the FF (termed the aberrant basaloid cell lining; ref. 50) is positive for both AECI and AECII markers (AQ5 and pSC, respectively) and predominantly expresses TGFB2.