Morphologically intact airways in lung fibrosis have an abnormal proteome

Abstract

Honeycombing is a histological pattern consistent with Usual Interstitial Pneumonia (UIP). Honeycombing refers to cystic airways located at sites of dense fibrosis with marked mucus accumulation. Utilizing laser capture microdissection coupled mass spectrometry (LCM-MS), we interrogated the fibrotic honeycomb airway cells and fibrotic uninvolved airway cells (distant from honeycomb airways and morphologically intact) in specimens from 10 patients with UIP. Non-fibrotic airway cell specimens from 6 patients served as controls. Furthermore, we performed LCM-MS on the mucus plugs found in 6 patients with UIP and 6 patients with mucinous adenocarcinoma. The mass spectrometry data were subject to both qualitative and quantitative analysis and validated by immunohistochemistry. Surprisingly, fibrotic uninvolved airway cells share a similar protein profile to honeycomb airway cells, showing deregulation of the slit and roundabout receptor (Slit and Robo) pathway as the strongest category. We find that (BPI) fold-containing family B member 1 (BPIFB1) is the most significantly increased secretome-associated protein in UIP, whereas Mucin-5AC (MUC5AC) is the most significantly increased in mucinous adenocarcinoma. We conclude that fibrotic uninvolved airway cells share pathological features with fibrotic honeycomb airway cells. In addition, fibrotic honeycomb airway cells are enriched in mucin biogenesis proteins with a marked derangement in proteins essential for ciliogenesis. This unbiased spatial proteomic approach generates novel and testable hypotheses to decipher fibrosis progression.

Structural mechanism of MUC5AC mucin net-like polymer formation and its SNP variability that affect risk of the lung diseases COPD and IPF

“…In the normal lung, the small airways without submucosal glands are characterized by surface goblet cells producing only MUC5B mucin (Hill et al, 2022;Okuda et al, 2021). However, recent observations suggest that the MUC5AC mucin is increased in peripheral airways in IPF (Herrera et al, 2023). The reason for the association of the MUC5B promotor SNP with IPF has been suggested to be due to increased levels of the MUC5B mucin (Hancock et al, 2018).…”

Pulmonary Toxicity Assessment after a Single Intratracheal Inhalation of Chlorhexidine Aerosol in Mice

“…The overexpression of Muc5b may cause mucociliary dysfunction, hypoxia, and host defense changes; then promote the destruction of lung structure and the loss of local homeostasis; and eventually lead to fibrosis [36,37]. Bpifa1 and Bpifb1 are increased in cystic fibrosis and IPF [38,39], which is the most significantly increased secretome-associated protein in UIP [40]. Therefore, for the lung fibrosis-like pathological changes caused by long-term exposure to chlorhexidine, effective intervention on mucociliary clearance may be a better treatment.…”

Role of Sensory Nerves in Pulmonary Fibrosis

“…Increased levels of sensory neuropeptides trigger inflammatory responses, mucus secretion, and bronchoconstriction [ 74 ], and the biogenesis of mucus is enhanced in PF [ 75 ]. CGRP itself is not an effective mediator of bronchoconstriction but can attenuate substance P-induced bronchoconstriction with a greater effect on distal (smaller) airways than proximal (larger) airways [ 76 ].…”