Matrix-driven Pneumocyte Differentiation

Lwebuga‐Mukasa, Jamson S.

doi:10.1164/ajrccm/144.2.452

Cited by 35 publications

(24 citation statements)

References 16 publications

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“…Abnormal epithelial morphology is also seen in constitutive integrin α3-null mice (Kreidberg et al, 1996) and lung epithelial-specific laminin α5-null mice (Nguyen et al, 2005). Different in vitro ECM culture conditions have been shown to alter lung epithelial cell differentiation with laminins promoting a type II cell phenotype, and fibronectin and collagen I inducing type I cell characteristics (Isakson et al, 2001;Lwebuga-Mukasa, 1991;Olsen et al, 2005;Rannels and Rannels, 1989). In addition to the ECM type, physical force mediated through integrin-ECM interactions regulate lung epithelial cell differentiation in vitro through unknown mechanisms (Huang et al, 2012;Sanchez-Esteban et al, 2004;Wang et al, 2013Wang et al, , 2006Wang et al, , 2009.…”

Section: Discussionmentioning

confidence: 99%

Epithelial β1 integrin is required for lung branching morphogenesis and alveolarization

et al. 2014

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Integrin-dependent interactions between cells and extracellular matrix regulate lung development; however, specific roles for β1-containing integrins in individual cell types, including epithelial cells, remain incompletely understood. In this study, the functional importance of β1 integrin in lung epithelium during mouse lung development was investigated by deleting the integrin from E10.5 onwards using surfactant protein C promoter-driven Cre. These mutant mice appeared normal at birth but failed to gain weight appropriately and died by 4 months of age with severe hypoxemia. Defects in airway branching morphogenesis in association with impaired epithelial cell adhesion and migration, as well as alveolarization defects and persistent macrophagemediated inflammation were identified. Using an inducible system to delete β1 integrin after completion of airway branching, we showed that alveolarization defects, characterized by disrupted secondary septation, abnormal alveolar epithelial cell differentiation, excessive collagen I and elastin deposition, and hypercellularity of the mesenchyme occurred independently of airway branching defects. By depleting macrophages using liposomal clodronate, we found that alveolarization defects were secondary to persistent alveolar inflammation. β1 integrin-deficient alveolar epithelial cells produced excessive monocyte chemoattractant protein 1 and reactive oxygen species, suggesting a direct role for β1 integrin in regulating alveolar homeostasis. Taken together, these studies define distinct functions of epithelial β1 integrin during both early and late lung development that affect airway branching morphogenesis, epithelial cell differentiation, alveolar septation and regulation of alveolar homeostasis.

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Section: Discussionmentioning

confidence: 99%

Epithelial β1 integrin is required for lung branching morphogenesis and alveolarization

et al. 2014

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“…However, our results are important for two reasons: first, they suggest that sHA in lung injury, regardless of origin, induces EMT in AT2 cells, thus leading to aberrant wound healing; second, our results indicate that treatments targeting solely fibroblasts may not be sufficient to abrogate VILI. AT2 cells are central elements in alveolar regeneration; they replenish the AT1 pool after injury (30), but can also contribute to aberrant wound healing. For example, targeted injury of AT2 cells induces pulmonary fibrosis in a mouse model (31) and AT2 EMT has been demonstrated in a mouse model of pulmonary fibrosis (9).…”

Section: Discussionmentioning

confidence: 99%

Mechanical Stretch Induces Epithelial-Mesenchymal Transition in Alveolar Epithelia via Hyaluronan Activation of Innate Immunity

Heise

Stober

Cheluvaraju

et al. 2011

Journal of Biological Chemistry

130

112

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Epithelial injury is a central event in the pathogenesis of many inflammatory and fibrotic lung diseases like acute respiratory distress syndrome, pulmonary fibrosis, and iatrogenic lung injury. Mechanical stress is an often underappreciated contributor to lung epithelial injury. Following injury, differentiated epithelia can assume a myofibroblast phenotype in a process termed epithelial to mesenchymal transition (EMT), which contributes to aberrant wound healing and fibrosis. We demonstrate that cyclic mechanical stretch induces EMT in alveolar type II epithelial cells, associated with increased expression of low molecular mass hyaluronan (sHA). We show that sHA is sufficient for induction of EMT in statically cultured alveolar type II epithelial cells and necessary for EMT during cell stretch. Furthermore, stretch-induced EMT requires the innate immune adaptor molecule MyD88. We examined the Wnt/␤-catenin pathway, which is known to mediate EMT. The Wnt target gene Wnt-inducible signaling protein 1 (wisp-1) is significantly up-regulated in stretched cells in hyaluronan-and MyD88-dependent fashion, and blockade of WISP-1 prevents EMT in stretched cells. In conclusion, we show for the first time that innate immunity transduces mechanical stress responses through the matrix component hyaluronan, and activation of the Wnt/␤-catenin pathway.Epithelial injury is now recognized as a primary event in the pathogenesis of lung disease (1). Alveolar cells consist of type I epithelia (AT1), 2 which serve gas exchange, and type II epithelia (AT2), which produce surfactant and are now recognized as the critical responders to lung injury. Although AT1 cells usually undergo cell death after critical injury, AT2 cells can present a variety of responses, including proinflammatory response, proliferation, differentiation to AT1 epithelia, or epithelial-tomesenchymal transition (EMT). The AT2 response to injury may ultimately lead to restoration of pulmonary architecture and function, or to dysregulated repair, fibrosis, and respiratory failure (2). The factors that promote regulated or pathological repair are incompletely understood. However, it is often forgotten that alveolar epithelia are not static cells. Alveolar epithelia undergo continuous cyclic stretch during ventilation; moreover, pathologically high levels of stretch are exerted on alveolar epithelia either as a consequence of injury (anatomical distortion from scarring) or iatrogenically (mechanical ventilation). The response of alveolar epithelia to injury must therefore be seen in the context of mechanical strain. The importance of stretch injury as a cause of lung disease is exemplified in the acute lung injury of critically ill patients, which is estimated at 200,000 cases in the United States annually (3). Mechanical ventilation is crucial for survival of these patients; however, it often leads to ventilator-induced lung injury (VILI) with pulmonary edema, inflammation, and fibrosis, leading to respiratory failure and death.Epithelial injury is central to the pa...

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“…Obecnie uznana hipoteza głosi, że samoistne włóknienie płuc jest wynikiem nieprawidło-wej interakcji pomiędzy komórkami nabłonka a komórkami podścieliska miąższu płuca oraz zaburzonego gojenia przewlekłych uszkodzeń nabłonka pęcherzyków, przy nieobecnych lub słabo wyrażonych zmianach zapalnych [7][8][9][10].…”

Section: Zapalenie W Ipfunclassified

“…Każde uszkodzenie tkanek w ustroju, zapoczątkowuje proces gojenia, czyli wytwarzania włóknistej blizny z włókien kolagenowych produkowanych przez fibroblasty [5,7,10]. Włóknienie miąższu płuca także jest skutkiem pobudzenia fibroblastów oraz tworzenia nieprawidłowych zło-gów kolagenu odpornych na degradację.…”

Section: Zapalenie W Ipfunclassified

“…Złożoność budowy anatomicznej i histologicznej płuc jest przyczyną istotnych trudności lub nawet całkowitej niemożności odbudowy prawidłowej struktury po masywnym uszkodzeniu. Jeśli prawidłowa odnowa jest niemożliwa, uszkodzone miejsca wypełniają się patologiczną tkanką włóknistą [3,5,7,10]. Poszczególne postaci idiopatycznych śród-miąższowych zapaleń płuc, różnią się rokowaniem oraz odpowiedzią na leczenie [1,3].…”

Section: Zapalenie W Ipfunclassified

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Immunopatogeneza Samoistnego Włóknienia Płuc

Demkow

2013

Advances in Respiratory Medicine

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The paper presents the state of the art in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Both, etiology and pathogenesis of IPF are unclear. The key elements in the pathogenesis of the disease are epithelial destruction and dysregulation of the phenotype of lung fibroblasts. Currently accepted hypothesis claims that IPF is not related to underlying inflammatory state but it is rather a result of pathological interaction between pulmonary epithelium and mesenchyme followed by disturbed healing of damaged alveolar epithelial cells. The function of lung progenitor cells residing in distant lung structures is also impaired. Some scientists claim that genetic defect causes fast shortening of telomeres reducing lung properties of regeneration. According to the current knowledge, IFP is a multifactorial disease resulting from a repeated cycle of injuries followed by pathological regeneration.

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Matrix-driven Pneumocyte Differentiation

Cited by 35 publications

References 16 publications

Epithelial β1 integrin is required for lung branching morphogenesis and alveolarization

Epithelial β1 integrin is required for lung branching morphogenesis and alveolarization

Mechanical Stretch Induces Epithelial-Mesenchymal Transition in Alveolar Epithelia via Hyaluronan Activation of Innate Immunity

Immunopatogeneza Samoistnego Włóknienia Płuc

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