New Mechanisms of Pulmonary Fibrosis

Strieter, Robert M.; Mehrad, Borna

doi:10.1378/chest.09-0510

Cited by 262 publications

(231 citation statements)

References 58 publications

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“…Fibroblasts and myofibroblasts are the predominant cell types involved in pulmonary fibrogenesis and can originate from local precursors such as interstitial fibroblasts, from EMT of abnormally activated alveolar epithelium, or from circulating fibrocytes derived from bone marrow recruited to the lung. 18,30 Three primary factors driving the differentiation of fibroblasts to myofibroblasts are high mechanical Figure 5 Src-deficient mice and PP2 abrogated lung stretch-induced epithelial-mesenchymal transition and Src phosphorylation in fibroblasts. Five days after administering bleomycin, representative micrographs ( Â 400) with a-smooth muscle actin (a-SMA, red), collagen I (Col I, bright green) and Hoechst (blue) immunofluorescent staining of fibroblasts (a) were from the nonventilated control mice and those subjected to V T at 30 ml/kg for 5 h with room air (n ¼ 5 per group).…”

Section: Discussionmentioning

confidence: 99%

“…3 EMT is characterized by loss of epithelial markers (E-cadherin, Zonula occludents (ZO)-1), cytoskeletal reorganization and transition to a spindle-shaped morphology concurrent with acquisition of mesenchymal markers (a-smooth muscle actin (a-SMA) and collagen I). 18 Mechanical stretchinduced activation of Src has recently been demonstrated to increase lung vascular permeability in mice. 13 Src protein tyrosine kinase family is categorized into nonreceptor tyrosine kinases and is one of the most crucial families for intracellular signal transduction related to cell proliferation, migration, differentiation and apoptotic cell death.…”

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confidence: 99%

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Mechanical ventilation augments bleomycin-induced epithelial–mesenchymal transition through the Src pathway

Liu

Kao

et al. 2014

Laboratory Investigation

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Mechanical ventilation used in patients with acute respiratory distress syndrome (ARDS) can damage pulmonary epithelial cells by producing inflammatory cytokines and depositing excess collagen. Src participates in plasminogen activator inhibitor-1 (PAI-1) and transforming growth factor-b1(TGF-b1) production during the fibroproliferative phase of ARDS, which involves a process of epithelial-mesenchymal transition (EMT). The mechanisms regulating interactions between mechanical ventilation and EMT are unclear. We hypothesized that EMT induced by high-tidal volume (V T ) mechanical stretch-augmented lung inflammation occurs through upregulation of the Src pathway. Five days after administering bleomycin to simulate acute lung injury (ALI), male C57BL/6 mice, either wild-type or Src-deficient, aged 3 months, weighing between 25 and 30 g, were exposed to low-V T (6 ml/kg) or high-V T (30 ml/kg) mechanical ventilation with room air for 1-5 h. Nonventilated mice were used as control subjects. We observed that high-V T mechanical ventilation increased microvascular permeability, PAI-1 and TGF-b1 protein levels, Masson's trichrome staining, extracellular collagen levels, collagen gene expression, fibroblast accumulation, positive staining of a-smooth muscle actin and type I collagen, activation of Src signaling and epithelial apoptotic cell death in wild-type mice (Po0.05). Decreased staining of the epithelial marker, Zonula occludents-1, was also observed. Mechanical stretch-augmented EMT and epithelial apoptosis were attenuated in Src-deficient mice and pharmacological inhibition of Src activity by PP2 (Po0.05). Our data suggest that high-V T mechanical ventilation-augmented EMT after bleomycin-induced ALI partially depends on the Src pathway. Acute respiratory distress syndrome (ARDS) is a disorder of acute respiratory failure and manifests as non-cardiogenic pulmonary edema, respiratory distress and hypoxemia. 1,2 Mechanical ventilation with high-tidal volume (V T ) causes severe lung injury (ventilator-induced lung injury (VILI)) characterized by an initial inhomogeneous inflammatory reaction or epithelial injury that is followed by a fibroproliferative phase with fibroblast proliferation. 3-8 Epithelialmesenchymal transition (EMT) is the differentiation of epithelial cells into myofibroblast-like cells, which contributes to the fibroproliferative phase. 3-8 Upregulating Src, the plasminogen activator inhibitor-1 (PAI-1), and the transforming growth factor-b1(TGF-b1) has recently been demonstrated to regulate EMT. 9-14 However, the mechanisms regulating the interactions between mechanical ventilation and EMT remain unclear.PAI-1, a member of the serine protease inhibitor (serpin) gene family, rapidly inhibits both the urokinase-type plasminogen activator and the tissue-type plasminogen activator (tPA). 15 Mice with homozygous deletion of PAI-1 were relatively protected from bleomycin-induced pulmonary fibrogenesis, whereas overexpression of PAI-1 enhanced pulmonary fibrogenesis. 9 As a primary profibrogenic cytokine...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Mechanical ventilation augments bleomycin-induced epithelial–mesenchymal transition through the Src pathway

Liu

Kao

et al. 2014

Laboratory Investigation

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“…This observation along with recognition of the importance of fibroblast foci in diagnosing UIP led to the current theory that acute lung injury is the primary event in the pathogenesis of UIP. 2,18,19 Fibroblast foci are small aggregates of fibroblasts and myofibroblasts that are present within myxoid stroma along the interstitium (Figure 8). 2 The spindle-shaped cells are arranged in layers parallel to the long axis of the alveolar septa beneath an epithelial lining composed of either hyperplastic type 2 pneumocytes or ciliated bronchiolar epithelium.…”

Section: Current Concepts Of Pathogenesis and Treatment Of Uipmentioning

confidence: 99%

“…There is extensive ongoing investigation into the molecular mechanisms leading to the development of fibrosis that are beyond the scope of this review, and these are summarized elsewhere. 18,19 Although inflammation is no longer considered the primary event in the development of UIP, it is important to remember that some degree of inflammation does occur as a secondary phenomenon, and it may further drive the development of fibrosis.…”

Section: Current Concepts Of Pathogenesis and Treatment Of Uipmentioning

confidence: 99%

Smoking-related interstitial fibrosis (SRIF), pathogenesis and treatment of usual interstitial pneumonia (UIP), and transbronchial biopsy in UIP

Katzenstein

2012

Modern Pathology

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This review focuses on three selected topics of current interest that are related to chronic fibrosing lung disorders and are important for pathologists. First, the clinical and pathologic features of smoking-related interstitial fibrosis (SRIF) are highlighted. SRIF is a common finding in smokers that has striking histologic changes but only mild associated clinical manifestations. It is characterized by marked alveolar septal fibrosis composed of a distinct form of hyalinized collagen deposition. The process is present mainly in subpleural and centrilobular parenchyma and is associated with emphysema and respiratory bronchiolitis. Second, important aspects of the pathogenesis and treatment of usual interstitial pneumonia (UIP) are reviewed. The current theory proposes that UIP is caused by tiny foci of acute lung injury (manifest pathologically by fibroblast foci) that occur and recur in the interstitium over many years. Inflammation may be present as a secondary phenomenon, but is not the primary cause, and therefore anti-inflammatory agents have little effect. The recurrent injury leads to permanent fibrosis, through a process that is considered to represent a form of abnormal wound healing. Multiple therapies have been attempted that are aimed largely at interrupting the fibrosing process, but none have been successful. The cause of the injury is unknown, but a role for aspiration due to gastroesophageal reflux is a popular current theory, and there is some evidence that anti-reflux therapy may be beneficial. Genetic predisposition has been implicated in the etiology of familial cases, and there is evidence that telomere shortening may be important in sporadic cases. Third, the use of transbronchial biopsy (TBB) in diagnosing UIP is reviewed. TBB can provide a surprising amount of information and is especially useful in certain situations, such as elderly or very sick patients in whom surgical lung biopsy carries increased morbidity and mortality.

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“…L'hypothèse principale est celle d'une lésion initiale de l'épithélium alvéolaire entraînant une augmentation des médiateurs qui stimulent l'inflammation et la prolifération des fibroblastes, associée à un échec des processus de réparation [21]. De nombreuses études ont montré l'importance du stress oxydant et sa participation à la physiopathologie de la fibrose pulmonaire [4].…”

Section: Agression Alvéolaireunclassified