Prostaglandin E2 and the Pathogenesis of Pulmonary FibrosisBozyk, Paul D.; Moore, Bethany B.
doi: 10.1165/rcmb.2011-0025rtpmid: 21421906
Prostaglandin (PG)E2 is a bioactive eicosanoid that regulates many biologically important processes in part due to its ability to signal through four distinct G-protein–coupled receptors with differential signaling activity and unique expression patterns in different cell types. Although PGE2 has been linked to malignancy in many organs, it is believed to play a beneficial role in the setting of fibrotic lung disease. This is in part due to the ability of PGE2 to limit many of the pathobiologic features of lung fibroblasts and myofibroblasts, including the ability of PGE2 to limit fibroblast proliferation, migration, collagen secretion, and, as originally reported in the Journal by us in 2003, the ability to limit transforming growth factor (TGF)-β–induced myofibroblast differentiation. In the setting of lung fibrosis, PGE2 production and signaling is often diminished. In the last 8 years, significant advances have been made to better understand the dysregulation of PGE2 production and signaling in the setting of lung fibrosis. We also have a clearer picture of how PGE2 inhibits myofibroblast differentiation and the receptor signaling pathways that can influence fibroblast proliferation. This review highlights these recent advances and offers new insights into the potential ways that PGE2 and its downstream signals can be regulated for therapeutic benefit in a disease that has no validated treatment options.
A Single Cell Functions as a Tissue-Specific Stem Cell and the In Vitro Niche-Forming CellGhosh, Moumita; Helm, Karen M.; Smith, Russell W.; Giordanengo, Matthew S.; Li, Bilan; Shen, Hongmei; Reynolds, Susan D.
doi: 10.1165/rcmb.2010-0314ocpmid: 21131442
Tissue-specific stem cell (TSC) behavior is determined by the stem cell niche. However, delineation of the TSC–niche interaction requires purification of both entities. We reasoned that the niche could be defined by the location of the TSC. We demonstrate that a single CD49fbright/Sca1+/ALDH+ basal cell generates rare label-retaining cells and abundant label-diluting cells. Label-retaining and label-diluting cells were located in the rimmed domain of a unique clone type, the rimmed clone. The TSC property of self-renewal was tested by serial passage at clonal density and analysis of clone-forming cell frequency. A single clone could be passaged up to five times and formed only rimmed clones. Thus, rimmed clone formation was a cell-intrinsic property. Differentiation potential was evaluated in air–liquid interface cultures. Homogenous cultures of rimmed clones were highly mitotic but were refractory to standard differentiation signals. However, rimmed clones that were cocultured with unfractionated tracheal cells generated each of the cell types found in the tracheal epithelium. Thus, the default niche is promitotic: Multipotential differentiation requires adaptation of the niche. Because lung TSCs are typically evaluated after injury, the behavior of CD49fbright/Sca1+/ALDH+ cells was tested in normal and naphthalene-treated mice. These cells were mitotically active in the normal and repaired epithelium, their proliferation rate increased in response to injury, and they retained label for 34 days. We conclude that the CD49fbright/Sca1+/ALDH+ tracheal basal cell is a TSC, that it generates its own niche in vitro, and that it participates in tracheal epithelial homeostasis and repair.
Keratinocyte Growth Factor Gene Transduction Ameliorates Pulmonary Fibrosis Induced by Bleomycin in MiceSakamoto, Seiko; Yazawa, Takuya; Baba, Yasuko; Sato, Hanako; Kanegae, Yumi; Hirai, Toyohiro; Saito, Izumu; Goto, Takahisa; Kurahashi, Kiyoyasu
doi: 10.1165/rcmb.2010-0092ocpmid: 21131445
Pulmonary fibrosis has high rates of mortality and morbidity, but there is no established therapy at present. We demonstrate here that bleomycin-induced pulmonary fibrosis in mice is ameliorated by intratracheal administration of keratinocyte growth factor (KGF)-expressing adenovirus vector. Progressive pulmonary fibrosis was created by continuous subcutaneous administration of 120 mg/kg of bleomycin subcutaneously using an osmotic pump twice from Day 1 to 7 and Day 29 to 35. The mice initially exhibited subpleural fibrosis and then exhibited advanced fibrosis in the parenchyma of the lungs. These histopathological changes were accompanied by reduced lung compliance (0.041 ± 0.011 versus 0.097 ± 0.004; P < 0.001), reduced messenger expression of surfactant proteins, and reduced KGF messenger expression in the lungs at 4 weeks compared with naive group. Intratracheal instillation of Ad-KGF at 1 week after the first administration of bleomycin increased KGF mRNA expression in the lungs compared with the fibrosis-induced mice that received saline alone. The phenotype was associated with alveolar epithelial cell proliferation, increased pulmonary compliance (0.062 ± 0.005 versus 0.041 ± 0.011; P = 0.023), and decreased mortality (survival rate on Day 56: 68.8% versus 0%; P = 0.002), compared with mice receiving only the saline vehicle. These observations suggest the therapeutic utility of a KGF-expressing adenoviral vector for pulmonary fibrosis.
Structure–Function Relations in an Elastase-Induced Mouse Model of EmphysemaHamakawa, Hiroshi; Bartolák-Suki, Erzsébet; Parameswaran, Harikrishnan; Majumdar, Arnab; Lutchen, Kenneth R.; Suki, Béla
doi: 10.1165/rcmb.2010-0473ocpmid: 21169554
Emphysema is a progressive disease characterized by the destruction of peripheral airspaces and subsequent decline in lung function. However, the relation between structure and function during disease progression is not well understood. The objective of this study was to assess the time course of the structural, mechanical, and remodeling properties of the lung in mice after elastolytic injury. At 2, 7, and 21 days after treatment with porcine pancreatic elastase, respiratory impedance, the constituents of lung extracellular matrix, and histological sections of the lung were evaluated. In the control group, no changes were observed in the structural or functional properties, whereas, in the treatment group, the respiratory compliance and its variability significantly increased by Day 21 (P < 0.001), and the difference in parameters decreased with increasing positive end-expiratory pressure. The heterogeneity of airspace structure gradually increased over time. Conversely, the relative amounts of elastin and type I collagen exhibited a peak (P < 0.01) at Day 2, but returned to baseline levels by Day 21. Structure–function relations manifested themselves in strong correlations between compliance parameters and both mean size and heterogeneity of airspace structure (r2 > 0.9). Similar relations were also obtained in a network model of the parenchyma in which destruction was based on the notion that mechanical forces contribute to alveolar wall rupture. We conclude that, in a mouse model of emphysema, progressive decline in lung function is sensitive to the development of airspace heterogeneity governed by local, mechanical, force-induced failure of remodeled collagen.
Glandular Gene Expression of Sinus Mucosa in Chronic Rhinosinusitis with and without Cystic FibrosisWu, Xiaofang; Peters-Hall, Jennifer R.; Ghimbovschi, Svetlana; Mimms, Remy; Rose, Mary C.; Peña, Maria T.
doi: 10.1165/rcmb.2010-0133ocpmid: 21177983
Secretory cells in submucosal glands (SMGs) secrete antibacterial proteins and mucin glycoproteins into the apical lumen of the respiratory tract, and these are critical for innate immune mucosal integrity. Glandular hyperplasia is manifested in diseases with obstructive respiratory pathologies associated with mucous hypersecretion, and is predominant in the sinus mucosa of patients with chronic rhinosinusitis (CRS), cystic fibrosis (CF), and clinical symptoms of CRS. To gain insights into the molecular basis of SMG hyperplasia in CRS, gene expression microarray analyses were performed to identify the differences in global and specific gene expression in the sinus mucosa of control, CRS, and CRS/CF patients. A marked up-regulation of 11 glandular-associated genes in CRS and CRS/CF sinus mucosa was evident. The RNA and protein expressions of the four most highly up-regulated genes (DSG3, KRT14, PTHLH, and OTX2) were evaluated. An increased expression of DSG3, KRT14, and PTHLH was demonstrated at the mRNA and protein levels in both CRS and CRS/CF sinus mucosa, whereas the increased expression of OTX2 was evident only for CRS/CF sinus mucosa, implicating OTX2 as a CF-specific gene. Immunofluorescence analysis localized DSG3, PTHLH, and OTX2 to serous cells, and KRT14 to myoepithelial cells, in SMGs. Because glandular hyperplasia is a central histologic feature of CRS, the identification of overexpressed glandular genes in the sinus mucosa lays the groundwork for future studies of glandular hyperplasia, and may ultimately lead to the development of novel treatments for mucous hypersecretion in patients with CRS.