Potential contribution of alveolar epithelial type I cells to pulmonary fibrosis

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Abstract

Pulmonary fibrosis (PF) is characterized by inflammation and fibrosis of the interstitium and destruction of alveolar histoarchitecture ultimately leading to a fatal impairment of lung function. Different concepts describe either a dominant role of inflammatory pathways or a disturbed remodeling of resident cells of the lung parenchyma during fibrogenesis. Further, a combination of both the mechanisms has been postulated. The present review emphasizes the particular involvement of alveolar epithelial type I cells in all these processes, their contribution to innate immune/inflammatory functions and maintenance of proper alveolar barrier functions. Amongst the different inflammatory and repair events the purinergic receptor P2X7, an ATP-gated cationic channel that regulates not only apoptosis, necrosis, autophagy, and NLPR3 inflammosome activation, but also the turnover of diverse tight junction (TJ) and water channel proteins, seems to be essential for the stability of alveolar barrier integrity and for the interaction with protective factors during lung injury.

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Short telomeres are a risk factor for idiopathic pulmonary fibrosis.

Jonathan Alder, Julian J L Chen, Lisa H. Lancaster … (2008)

Idiopathic interstitial pneumonias (IIPs) have a progressive and often fatal course, and their enigmatic etiology has complicated approaches to effective therapies. Idiopathic pulmonary fibrosis (IPF) is the most common of IIPs and shares with IIPs an increased incidence with age and unexplained scarring in the lung. Short telomeres limit tissue renewal capacity in the lung and germ-line mutations in telomerase components, hTERT and hTR, underlie inheritance in a subset of families with IPF. To examine the hypothesis that short telomeres contribute to disease risk in sporadic IIPs, we recruited patients who have no family history and examined telomere length in leukocytes and in alveolar cells. To screen for mutations, we sequenced hTERT and hTR. We also reviewed the cases for features of a telomere syndrome. IIP patients had shorter leukocyte telomeres than age-matched controls (P < 0.0001). In a subset (10%), IIP patients had telomere lengths below the first percentile for their age. Similar to familial cases with mutations, IPF patients had short telomeres in alveolar epithelial cells (P < 0.0001). Although telomerase mutations were rare, detected in 1 of 100 patients, we identified a cluster of individuals (3%) with IPF and cryptogenic liver cirrhosis, another feature of a telomere syndrome. Short telomeres are thus a signature in IIPs and likely play a role in their age-related onset. The clustering of cryptogenic liver cirrhosis with IPF suggests that the telomere shortening we identify has consequences and can contribute to what appears clinically as idiopathic progressive organ failure in the lung and the liver.

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Expression of endothelin-1 in the lungs of patients with pulmonary hypertension.

A Giaid, M Yanagisawa, D. Langleben … (1993)

Pulmonary hypertension is characterized by an increase in vascular tone or an abnormal proliferation of muscle cells in the walls of small pulmonary arteries. Endothelin-1 is a potent endothelium-derived vasoconstrictor peptide with important mitogenic properties. It has therefore been suggested that endothelin-1 may contribute to increases in pulmonary arterial tone or smooth-muscle proliferation in patients with pulmonary hypertension. We studied the sites and magnitude of endothelin-1 production in the lungs of patients with various causes of pulmonary hypertension. We studied the distribution of endothelin-1-like immunoreactivity (by immunocytochemical analysis) and endothelin-1 messenger RNA (by in situ hybridization) in lung specimens from 15 control subjects, 11 patients with plexogenic pulmonary arteriopathy (grades 4 through 6), and 17 patients with secondary pulmonary hypertension and pulmonary arteriopathy of grades 1 through 3. In the controls, endothelin-1-like immunoreactivity was rarely seen in vascular endothelial cells. In the patients with pulmonary hypertension, endothelin-1-like immunoreactivity was abundant, predominantly in endothelial cells of pulmonary arteries with medial thickening and intimal fibrosis. Likewise, endothelin-1 messenger RNA was increased in the patients with pulmonary hypertension and was expressed primarily at sites of endothelin-1-like immunoreactivity. There was a strong correlation between the intensity of endothelin-1-like immunoreactivity and pulmonary vascular resistance in the patients with plexogenic pulmonary arteriopathy, but not in those with secondary pulmonary hypertension. Pulmonary hypertension is associated with the increased expression of endothelin-1 in vascular endothelial cells, suggesting that the local production of endothelin-1 may contribute to the vascular abnormalities associated with this disorder.

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Induction of epithelial-mesenchymal transition in alveolar epithelial cells by transforming growth factor-beta1: potential role in idiopathic pulmonary fibrosis.

Brigham C Willis, Janice M Liebler, Katherine Luby-Phelps … (2005)

The hallmark of idiopathic pulmonary fibrosis (IPF) is the myofibroblast, the cellular origin of which in the lung is unknown. We hypothesized that alveolar epithelial cells (AECs) may serve as a source of myofibroblasts through epithelial-mesenchymal transition (EMT). Effects of chronic exposure to transforming growth factor (TGF)-beta1 on the phenotype of isolated rat AECs in primary culture and a rat type II cell line (RLE-6TN) were evaluated. Additionally, tissue samples from patients with IPF were evaluated for cells co-expressing epithelial (thyroid transcription factor (TTF)-1 and pro-surfactant protein-B (pro-SP-B), and mesenchymal (alpha-smooth muscle actin (alpha-SMA)) markers. RLE-6TN cells exposed to TGF-beta1 for 6 days demonstrated increased expression of mesenchymal cell markers and a fibroblast-like morphology, an effect augmented by tumor necrosis factor-alpha (TNF-alpha). Exposure of rat AECs to TGF-beta1 (100 pmol/L) resulted in increased expression of alpha-SMA, type I collagen, vimentin, and desmin, with concurrent transition to a fibroblast-like morphology and decreased expression of TTF-1, aquaporin-5 (AQP5), zonula occludens-1 (ZO-1), and cytokeratins. Cells co-expressing epithelial markers and alpha-SMA were abundant in lung tissue from IPF patients. These results suggest that AECs undergo EMT when chronically exposed to TGF-beta1, raising the possibility that epithelial cells may serve as a novel source of myofibroblasts in IPF.

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Author and article information

Journal

Journal ID (nlm-ta): Biosci Rep

Journal ID (iso-abbrev): Biosci. Rep

Journal ID (hwp): ppbioscirep

Journal ID (publisher-id): BSR

Title: Bioscience Reports

Publisher: Portland Press Ltd.

ISSN (Print): 0144-8463

ISSN (Electronic): 1573-4935

Publication date (Electronic preprint): 12 October 2017

Publication date (Electronic): 21 November 2017

Publication date Collection: 22 December 2017

Volume: 37

Issue: 6

Electronic Location Identifier: BSR20171301

Affiliations

Medical Faculty ‘Carl Gustav Carus’, Institute of Anatomy, Technical University of Dresden, Fetscherstr. 74, Dresden D-01307, Germany

Author notes

Correspondence: Michael Kasper ( michael.kasper@ 123456tu-dresden.de )

Article

DOI: 10.1042/BSR20171301

PMC ID: 5696455

PubMed ID: 29026006

SO-VID: 6163b45c-7752-49c2-8233-fcc07bb48054

License:

This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY).

History

Date received : 17 August 2017

Date revision received : 28 September 2017

Date accepted : 29 September 2017

Page count

Pages: 18

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Potential contribution of alveolar epithelial type I cells to pulmonary fibrosis

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Universal stem cells

Most cited references 179

Short telomeres are a risk factor for idiopathic pulmonary fibrosis.

Expression of endothelin-1 in the lungs of patients with pulmonary hypertension.

Induction of epithelial-mesenchymal transition in alveolar epithelial cells by transforming growth factor-beta1: potential role in idiopathic pulmonary fibrosis.

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Cited by 28

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