Cell-specific Gene Expression in Patients with Usual Interstitial Pneumonia

Kelly, Margaret M.; Leigh, Richard; Gilpin, Sarah E.; Cheng, Elaine; Martin, Gail; Radford, Katherine; Cox, Gerard; Gauldie, Jack

doi:10.1164/rccm.200510-1648oc

Cited by 40 publications

(35 citation statements)

References 80 publications

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“…In a previous study also using LCM, in which only few MMPs were included, it was found that MMP-9 and MMP-7 were up-regulated in the epithelium adjacent to fibroblastic foci (33). MMP-1 and MMP-7 have been proposed as potential peripheral blood biomarkers in IPF (17), and MMP-7 increases in the plasma are predictive of significantly worse prognosis in IPF (34).…”

Section: Discussionmentioning

confidence: 99%

Matrix Metalloproteinase-19 Is a Key Regulator of Lung Fibrosis in Mice and Humans

Kovkarova-Naumovski²,

Jara³

et al. 2012

Am J Respir Crit Care Med

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Rationale: Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by epithelial phenotypic changes and fibroblast activation. Based on the temporal heterogeneity of IPF, we hypothesized that hyperplastic alveolar epithelial cells regulate the fibrotic response. Objectives: To identify novel mediators of fibrosis comparing the transcriptional signature of hyperplastic epithelial cells and conserved epithelial cells in the same lung. Methods: Laser capture microscope and microarrays analysis were used to identify differentially expressed genes in IPF lungs. Bleomycininduced lung fibrosis was evaluated in Mmp19-deficient and wild-type (WT) mice. The role of matrix metalloproteinase (MMP)-19 was additionally studied by transfecting the human MMP19 in alveolar epithelial cells. Measurements and Main Results: Laser capture microscope followed by microarray analysis revealed a novel mediator, MMP-19, in hyperplastic epithelial cells adjacent to fibrotic regions. Mmp19 2/2 mice showed a significantly increased lung fibrotic response to bleomycin compared with WT mice. A549 epithelial cells transfected with human MMP19 stimulated wound healing and cell migration, whereas silencing MMP19 had the opposite effect. Gene expression microarray of transfected A549 cells showed that PTGS2 (prostaglandin-endoperoxide synthase 2) was one of the highly induced genes. PTGS2 was overexpressed in IPF lungs and colocalized with MMP-19 in hyperplastic epithelial cells. In WT mice, PTGS2 was significantly increased in bronchoalveolar lavage and lung tissues after bleomycin-induced fibrosis, but not in Mmp19 2/2 mice. Inhibition of Mmp-19 by siRNA resulted in inhibition of Ptgs2 at mRNA and protein levels. Conclusions: Up-regulation of MMP19 induced by lung injury may play a protective role in the development of fibrosis through the induction of PTGS2.

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Section: Discussionmentioning

confidence: 99%

Matrix Metalloproteinase-19 Is a Key Regulator of Lung Fibrosis in Mice and Humans

Kovkarova-Naumovski²,

Jara³

et al. 2012

Am J Respir Crit Care Med

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“…We, however, concern about false-positive immunohistochemical staining in Willis et al (2005), since there are a lot of granular staining in epithelial cells, quite unusual for smooth muscle actin. Recently, Kelly et al (2006) demonstrated that the expression of -SMA mRNA or protein was not detected in epithelial cells overlying Wbroblastic foci in IPF obtained by laser capture microdissection. It is possible that EMT is transient during some speciWc stage of Wbrogenesis, and we could not Wnd double positive cells.…”

Section: Discussionmentioning

confidence: 99%

Dual-immunohistochemistry provides little evidence for epithelial–mesenchymal transition in pulmonary fibrosis

Yamada

Kuwano

Maeyama

et al. 2008

Histochem Cell Biol

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Epithelial-mesenchymal transition (EMT) has been considered to be involved in organ fibrogenesis. However, there is few direct evidence of this process in the pathophysiology of pulmonary fibrosis in vivo. Therefore, we tried to verify the involvement of this process in the development of pulmonary fibrosis. Since the co-expressions of epithelial and mesenchymal markers are thought to be a marker of EMT, we performed dual-immuunohistochemistry to assess the co-expressions of these proteins in lung tissues from bleomycin-induced pulmonary fibrosis in mice, and from patients with idiopathic pulmonary fibrosis, and nonspecific interstitial pneumonia. Double positive cells for epithelial markers including E-cadherin, T1alpha, or aquaporin 5, and a mesenchymal markers alpha-smooth muscle actin or vimentin were not found in bleomycin-induced pulmonary fibrosis in mice. Double positive cells for E-cadherin, ICAM-1, LEA, CD44v9, or SP-A and alpha-smooth muscle actin or vimentin were not found in lung tissues from normal lung parenchyma, idiopathic pulmonary fibrosis and nonspecific interstitial pneumonia. These results offer at least two possibilities. One is that EMT does not occur in IPF or bleomycin-induced pulmonary fibrosis in mice. Another is that EMT may occur in pulmonary fibrosis but the time during this transition in which cells express detectable levels of epithelial and mesenchymal markers is too small to be detected by double immunohistochemistry.

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“…In vitro studies and immunohistochemical analyses have shown that IPF fibroblasts themselves are a significant source of many of these cytokines and chemokines, which can then act in an autocrine manner. Fibroblasts derived from IPF lungs are also characterized by dysregulated expression of metalloproteinases and their inhibitors [84], which likely contributes to the deranged tissue remodeling seen in IPF. In addition, they exhibit decreased ability to upregulate COX-2 expression, resulting in reduced production of prostaglandin E2 (PGE2), an inhibitor of fibroblast migration, proliferation, collagen production, and myofibroblast differentiation.…”

Section: Fibroblast Behaviormentioning

confidence: 99%

Idiopathic Pulmonary Fibrosis—an Epidemiological and Pathological Review

Borchers

Chang²,

Keen

et al. 2010

Clinic Rev Allerg Immunol

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Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease (ILD) affecting the pulmonary interstitium. Other forms of interstitial lung disease exist, and in some cases, an environmental etiology can be delineated. The diagnosis of IPF is typically established by high-resolution CT scan. IPF tends to have a worse prognosis than other forms of ILD. Familial cases of IPF also exist, suggesting a genetic predisposition; telomerase mutations have been observed to occur in familial IPF, which may also explain the increase in IPF with advancing age. Alveolar epithelial cells are believed to be the primary target of environmental agents that have been putatively associated with IPF. These agents may include toxins, viruses, or the autoantibodies found in collagen vascular diseases. The mechanism of disease is still unclear in IPF, but aberrations in fibroblast differentiation, activation, and proliferation may play a role. Epithelial-mesenchymal transition may also be an important factor in the pathogenesis, as it may lead to accumulation of fibroblasts in the lung and a disruption of normal tissue structure. Abnormalities in other components of the immune system, including T cells, B cells, and dendritic cells, as well as the development of ectopic lymphoid tissue, have also been observed to occur in IPF and may play a role in the stimulation of fibrosis that is a hallmark of the disease. It is becoming increasingly clear that the pathogenesis of IPF is indeed a complex and convoluted process that involves numerous cell types and humoral factors.

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Cell-specific Gene Expression in Patients with Usual Interstitial Pneumonia

Abstract: Altered gene expression of important profibrotic mediators in the different cellular lung compartments in patients with UIP likely plays an important role in pathogenesis of the deranged extracellular matrix deposition and subsequent fibrosis in this condition.

Cited by 40 publications

References 80 publications

Matrix Metalloproteinase-19 Is a Key Regulator of Lung Fibrosis in Mice and Humans

Matrix Metalloproteinase-19 Is a Key Regulator of Lung Fibrosis in Mice and Humans

Dual-immunohistochemistry provides little evidence for epithelial–mesenchymal transition in pulmonary fibrosis

Idiopathic Pulmonary Fibrosis—an Epidemiological and Pathological Review

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