The Alveolar Epithelium and Pulmonary Fibrosis
TL;DR: The advances in recent studies on the role of the alveolar epithelium in pulmonary fibrosis are reviewed, including studies suggesting that the activation of the AECs may play an active role in the pathogenesis ofmonary fibrosis.
Abstract: Idiopathic interstitial pneumonias (IIPs) are a heterogeneous group of diffuse pulmonary parenchymal diseases that are comprised of seven distinct clinical and pathological entities. Idiopathic pulmonary fibrosis (IPF) and cryptogenic organizing pneumonia (COP) represent two of the most prevalent members of the disease group with major differences in their pathogenesis, clinical course and prognosis. IPF is a refractory and lethal IIP characterized by fibroblast prolifera- tion, deposition of extracellular matrix (ECM) and progressive lung scarring. The incidence of IPF is estimated at 15 to 40 cases per 100,000 per year, and the mean survival from the time of diagnosis is 3 to 5 years regardless of treatment. While its pathogenesis is incompletely understood, the currently accepted paradigm proposes that injury of the alveolar epithe- lium is followed by a burst of pro-inflammatory and fibroproliferative mediators that invoke responses associated with dysregulated repair of the damaged alveolar epithelium. Recently, there have been studies suggesting that the activation of the alveolar epithelial cells (AECs) may play an active role in the pathogenesis of pulmonary fibrosis. Here, we review the advances in recent studies on the role of the alveolar epithelium in pulmonary fibrosis. AECS: A BRIEF OVERVIEW OF STRUCTURE AND PHYSIOLOGICAL FUNCTIONS Two types of AECs populate the alveolar epithelium in normal adult lungs, alveolar epithelial type I (AT I) and al- veolar epithelial type II (AT II) cells. AT I pneumocytes comprise 40% of the AECs and cover 90% of the internal surface area of the lung. AT I cells are highly attenuated and form an interface with pulmonary capillaries that are inti- mately involved in gas exchange. These cells also take part in peptide and amino acid transportation across the lung by pinocytosis and transporter-mediated transport (1). Recently, AT I cells have been shown to be also important in the trans- portation of water and sodium across the lung (2, 3). AT II cells, on the other hand, AT II cells make up 16% of the parenchymal cells in the lung and account for only 5% of the alveolar surface. These cells are cuboidal cells that are situated between AT I cells and they contain characteristic lamellar bodies and apical microvilli. AT II cells synthesize, store and secrete the pulmonary surfactant (PS), which con- sists of lipids and their associated proteins and whose func- tion is to reduce the surface tension of the lung alveolus and prevent it from collapse or overdistension with respiration. AT II cells also regulate alveolar fluid balance in normal lungs and during the resolution of pulmonary edema (4) and the pathogenesis of acute lung injury with pulmonary edema is associated with an insufficient number of AT II cells and transportation of water into the lung alveolus. Recently, AT II cells have been shown to synthesize and secrete immuno- modulatory proteins important for host defense, including surfactant proteins A (SP-A) and D (SP-D) (5). SP-A can combine with lipid A in the lipopolysaccharide on the sur- face of bacterium and it also regulates the activities of
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01 Jan 1996
TL;DR: In this paper, the authors found that the proliferation of type II pneumocytes occurs during the early phase of acute lung injury and is of variable extent and duration, and the time frame within which the apoptotic response occurs is variable and is likely to be dependent upon the specific etiology and extent of the injury.
Abstract: Proliferation of type II pneumocytes has been linked to a repair process during the early phase of acute lung injury, and it persists for a variable period. The mechanisms responsible for their dissolution and/or disappearance are not known, but we speculate that it may be partly due to apoptosis. Sections of lung tissue from patients with acute lung injury (n = 7) and chronic interstitial pneumonia (n = 14) were stained for detection of apoptotic cells via specific labeling of nuclear DNA fragmentation. Results were correlated with those of proliferating cell nuclear antigen (PCNA) staining for cell proliferation. Marked apoptosis of CD68-negative type II pneumocytes (30 to 80%) was detected in four of the seven (57%) cases of acute lung injury. In these cases, representing the resolution phase of acute lung injury, PCNA positivity in pneumocytes was extremely rare. In the 3 other cases in the acute/proliferative phase, apoptotic type II pneumocytes were rare whereas PCNA expression was quite evident in these cells. In chronic interstitial pneumonia, only rare type II pneumocytes (<5%) exhibited apoptosis, and they showed variable staining for PCNA (up to 70%). We conclude that proliferation of type II pneumocytes occurs during the early phase of acute lung injury and is of variable extent and duration. In the resolution phase of acute lung injury, extensive apoptosis of type II pneumocytes is largely responsible for the disappearance of these cells. The time frame within which the apoptotic response occurs is variable and is likely to be dependent upon the specific etiology and extent of the injury. In chronic interstitial pneumonia, type II pneumocytes proliferate continuously, although to a much lesser degree than in the early phase of acute lung injury, and are minimally apoptotic.
237 citations
TL;DR: Treatment with Earthworm extract was found to be a potential anti-oxidative, anti-inflammatory, and anti-fibrotic drug for silicosis and it is demonstrated that Nrf2 activation partly mediates the interventional effects of EE against SiO2-induced pulmonary fibrosis.
24 citations
TL;DR: The data suggest that Kif7 may function to regulate the maintenance of the respiratory airway architecture by controlling cellular density, cell proliferation, and cycle exit through its role as a microtubule associated protein.
Abstract: The cell cycle must be tightly coordinated for proper control of embryonic development and for the long-term maintenance of organs such as the lung. There is emerging evidence that Kinesin family member 7 (Kif7) promotes Hedgehog (Hh) signaling during embryonic development, and its misregulation contributes to diseases such as ciliopathies and cancer. Kif7 encodes a microtubule interacting protein that controls Hh signaling through regulation of microtubule dynamics within the primary cilium. However, whether Kif7 has a function in nonciliated cells remains largely unknown. The role Kif7 plays in basic cell biological processes like cell proliferation or cell cycle progression also remains to be elucidated. Here, we show that Kif7 is required for coordination of the cell cycle, and inactivation of this gene leads to increased cell proliferation in vivo and in vitro. Immunostaining and transmission electron microscopy experiments show that Kif7dda/dda mutant lungs are hyperproliferative and exhibit reduced alveolar epithelial cell differentiation. KIF7 depleted C3H10T1/2 fibroblasts and Kif7dda/dda mutant mouse embryonic fibroblasts have increased growth rates at high cellular densities, suggesting that Kif7 may function as a general regulator of cellular proliferation. We ascertained that in G1, Kif7 and microtubule dynamics regulate the expression and activity of several components of the cell cycle machinery known to control entry into S phase. Our data suggest that Kif7 may function to regulate the maintenance of the respiratory airway architecture by controlling cellular density, cell proliferation, and cycle exit through its role as a microtubule associated protein.
9 citations
Cites background from "The Alveolar Epithelium and Pulmona..."
...The alveolar epithelium needs to be maintained throughout life as it can be damaged by pathogens, environmental toxins, and various disease processes [1,2]....
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TL;DR: The results support the possibility of GSE as an effective, safe anti-inflammatory dietary supplement to attenuate the pathogenicity of asthma and suggest a role for GSE in asthma remodeling.
7 citations
References
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TL;DR: The hypothesis that idiopathic pulmonary fibrosis is a fibrotic rather than an inflammatory disease is examined, and the therapeutic implications of these findings are discussed.
Abstract: Idiopathic pulmonary fibrosis is a progressive and usually fatal lung disease characterized by fibroblast proliferation and extracellular matrix remodeling, which result in irreversible distortion of the lung's architecture. Although the pathogenetic mechanisms remain to be determined, the prevailing hypothesis holds that fibrosis is preceded and provoked by a chronic inflammatory process that injures the lung and modulates lung fibrogenesis, leading to the end-stage fibrotic scar. However, there is little evidence that inflammation is prominent in early disease, and it is unclear whether inflammation is relevant to the development of the fibrotic process. Evidence suggests that inflammation does not play a pivotal role. Inflammation is not a prominent histopathologic finding, and epithelial injury in the absence of ongoing inflammation is sufficient to stimulate the development of fibrosis. In addition, the inflammatory response to a lung fibrogenic insult is not necessarily related to the fibrotic response. Clinical measurements of inflammation fail to correlate with stage or outcome, and potent anti-inflammatory therapy does not improve outcome. This review presents a growing body of evidence suggesting that idiopathic pulmonary fibrosis involves abnormal wound healing in response to multiple, microscopic sites of ongoing alveolar epithelial injury and activation associated with the formation of patchy fibroblast-myofibroblast foci, which evolve to fibrosis. Progress in understanding the fibrogenic mechanisms in the lung is likely to yield more effective therapies.
1,696 citations
"The Alveolar Epithelium and Pulmona..." refers background in this paper
...An alternative hypothesis has been proposed that IPF likely results from an aberrant activation of AVEs after injury that provoke the migration, proliferation, and abnormal activation of mesenchymal cells, leading to the exaggerated accumulation of ECM with an irreversible destruction of the pulmonary parenchyma [58-60]....
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...Recently, the possibility that AECs may transdifferentiate into fibroblasts/ myofibroblasts has gained attention [58, 64]....
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TL;DR: It is demonstrated that transient overexpression of active, but not latent, TGF-beta1 resulted in prolonged and severe interstitial and pleural fibrosis characterized by extensive deposition of the extracellular matrix proteins collagen, fibronectin, and elastin and by emergence of cells with the myofibroblast phenotype.
Abstract: Transforming growth factor (TGF)-beta1 has been implicated in the pathogenesis of fibrosis based upon its matrix-inducing effects on stromal cells in vitro, and studies demonstrating increased expression of total TGF-beta1 in fibrotic tissues from a variety of organs. The precise role in vivo of this cytokine in both its latent and active forms, however, remains unclear. Using replication-deficient adenovirus vectors to transfer the cDNA of porcine TGF-beta1 to rat lung, we have been able to study the effect of TGF-beta1 protein in the respiratory tract directly. We have demonstrated that transient overexpression of active, but not latent, TGF-beta1 resulted in prolonged and severe interstitial and pleural fibrosis characterized by extensive deposition of the extracellular matrix (ECM) proteins collagen, fibronectin, and elastin, and by emergence of cells with the myofibroblast phenotype. These results illustrate the role of TGF-beta1 and the importance of its activation in the pulmonary fibrotic process, and suggest that targeting active TGF-beta1 and steps involved in TGF-beta1 activation are likely to be valuable antifibrogenic therapeutic strategies. This new and versatile model of pulmonary fibrosis can be used to study such therapies.
990 citations
"The Alveolar Epithelium and Pulmona..." refers methods or result in this paper
...used active TGF- transgene to induce lung fibrosis in rats and found that inflammation was present and peaked before maximal fibrosis [18]....
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...showed that TGF- transgeene promoted lung fibrosis in rats [18] and similar findings were also obtained in mice that overexpression of TGF- promoted lung fibrosis [26]....
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TL;DR: It is hoped that this review will stimulate further consideration of the cellular mechanisms of fibrogenesis in the lung and especially the role of the epithelium in this process, potentially leading to innovative avenues of investigation and treatment.
Abstract: Epithelial-mesenchymal transition (EMT), a process whereby fully differentiated epithelial cells undergo transition to a mesenchymal phenotype giving rise to fibroblasts and myofibroblasts, is increasingly recognized as playing an important role in repair and scar formation following epithelial injury. The extent to which this process contributes to fibrosis following injury in the lung is a subject of active investigation. Recently, it was demonstrated that transforming growth factor (TGF)-β induces EMT in alveolar epithelial cells (AEC) in vitro and in vivo, and epithelial and mesenchymal markers have been colocalized to hyperplastic type II (AT2) cells in lung tissue from patients with idiopathic pulmonary fibrosis (IPF), suggesting that AEC may exhibit extreme plasticity and serve as a source of fibroblasts and/or myofibroblasts in lung fibrosis. In this review, we describe the characteristic features of EMT and its mechanistic underpinnings. We further describe the contribution of EMT to fibrosis in adult tissues following injury, focusing especially on the critical role of TGF-β and its downstream mediators in this process. Finally, we highlight recent descriptions of EMT in the lung and the potential implications of this process for the treatment of fibrotic lung disease. Treatment for fibrosis of the lung in diseases such as IPF has heretofore focused largely on amelioration of potential inciting processes such as inflammation. It is hoped that this review will stimulate further consideration of the cellular mechanisms of fibrogenesis in the lung and especially the role of the epithelium in this process, potentially leading to innovative avenues of investigation and treatment.
906 citations
"The Alveolar Epithelium and Pulmona..." refers background in this paper
...Willis and colleagues have shown that AECs may serve as a novel source of myofibroblasts in IPF through the epithelial mesenchymal transition under stimulation by TGF- [65, 66] and this finding has also been shown by others [67, 68]....
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TL;DR: The 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.
Abstract: 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)-β1 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 (α-smooth muscle actin (α-SMA)) markers. RLE-6TN cells exposed to TGF-β1 for 6 days demonstrated increased expression of mesenchymal cell markers and a fibroblast-like morphology, an effect augmented by tumor necrosis factor-α (TNF-α). Exposure of rat AECs to TGF-β1 (100 pmol/L) resulted in increased expression of α-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 α-SMA were abundant in lung tissue from IPF patients. These results suggest that AECs undergo EMT when chronically exposed to TGF-β1, raising the possibility that epithelial cells may serve as a novel source of myofibroblasts in IPF.
896 citations
"The Alveolar Epithelium and Pulmona..." refers background in this paper
...TGF- consists of a highly homologous group of multifunctional regulatory peptides that are differentially expressed and involved in the control of cell growth, differentiation, morphogenesis and ECM remodeling and is the most potent and efficacious cytokine in promoting fibrosis....
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...PDGF regulates TGF- 1 and TNF- and actively contributes to pulmonary fibrosis....
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...Sime et al. used active TGF- transgene to induce lung fibrosis in rats and found that inflammation was present and peaked before maximal fibrosis [18]....
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...Sime et al. showed that TGF- transgeene promoted lung fibrosis in rats [18] and similar findings were also obtained in mice that overexpression of TGF- promoted lung fibrosis [26]....
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...HGF has been shown to inhibit the progression of bleomycin-induced pulmonary fibrosis in mice, which may be due to inhibition by HGF of TGF- signaling through induction of Smad-7, an inhibitor of TGFsignaling [39]....
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TL;DR: The data showed that TGF-β1 induced A549 cells with an alveolar epithelial type II cell phenotype to undergo EMT in a time-and concentration-dependent manner, and cells that had undergone EMT showed enhanced expression of markers of fibrogenesis including collagens type I and III and CTGF.
Abstract: Fibroblastic foci are characteristic features in lung parenchyma of patients with idiopathic pulmonary fibrosis (IPF). They comprise aggregates of mesenchymal cells which underlie sites of unresolved epithelial injury and are associated with progression of fibrosis. However, the cellular origins of these mesenchymal phenotypes remain unclear. We examined whether the potent fibrogenic cytokine TGF-β1 could induce epithelial mesenchymal transition (EMT) in the human alveolar epithelial cell line, A549, and investigated the signaling pathway of TGF-β1-mediated EMT. A549 cells were examined for evidence of EMT after treatment with TGF-β1. EMT was assessed by: morphology under phase-contrast microscopy; Western analysis of cell lysates for expression of mesenchymal phenotypic markers including fibronectin EDA (Fn-EDA), and expression of epithelial phenotypic markers including E-cadherin (E-cad). Markers of fibrogenesis, including collagens and connective tissue growth factor (CTGF) were also evaluated by measuring mRNA level using RT-PCR, and protein by immunofluorescence or Western blotting. Signaling pathways for EMT were characterized by Western analysis of cell lysates using monoclonal antibodies to detect phosphorylated Erk1/2 and Smad2 after TGF-β1 treatment in the presence or absence of MEK inhibitors. The role of Smad2 in TGF-β1-mediated EMT was investigated using siRNA. The data showed that TGF-β1, but not TNF-α or IL-1β, induced A549 cells with an alveolar epithelial type II cell phenotype to undergo EMT in a time-and concentration-dependent manner. The process of EMT was accompanied by morphological alteration and expression of the fibroblast phenotypic markers Fn-EDA and vimentin, concomitant with a downregulation of the epithelial phenotype marker E-cad. Furthermore, cells that had undergone EMT showed enhanced expression of markers of fibrogenesis including collagens type I and III and CTGF. MMP-2 expression was also evidenced. TGF-β1-induced EMT occurred through phosphorylation of Smad2 and was inhibited by Smad2 gene silencing; MEK inhibitors failed to attenuate either EMT-associated Smad2 phosphorylation or the observed phenotypic changes. Our study shows that TGF-β1 induces A549 alveolar epithelial cells to undergo EMT via Smad2 activation. Our data support the concept of EMT in lung epithelial cells, and suggest the need for further studies to investigate the phenomenon.
711 citations
"The Alveolar Epithelium and Pulmona..." refers background in this paper
...Willis and colleagues have shown that AECs may serve as a novel source of myofibroblasts in IPF through the epithelial mesenchymal transition under stimulation by TGF- [65, 66] and this finding has also been shown by others [67, 68]....
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