Effects of KGF on Alveolar Epithelial Cell Transdifferentiation Are Mediated by JNK Signaling

Qiao, Renli; Wang, Yan; Clavijo, Carlos; Mehrian‐Shai, Ruty; Kim, Kwang‐Jin; Ann, David K.; Crandall, Edward D.; Borok, Zea

doi:10.1165/rcmb.2007-0172oc

Cited by 37 publications

(42 citation statements)

References 42 publications

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“…Previous studies have shown that AQP5 is a marker of AECI, and SP-C is a marker of AECII (6,10). In the present study, our evaluation showed that KGF promoted transdifferentiation of AECIIs, as well as making AECIs revert to AECIIs.…”

Section: Discussionsupporting

confidence: 69%

“…It is well established that alveolar epithelial type II cells (AECIIs) serve to defend the alveoli, and their functions include synthesis and secretion of pulmonary surfactant, activation of ion transport, and maintenance and repair of alveolar epithelium after lung injury (6). Primary AECIIs cultured over a period of 3 to 4 days gradually transdifferentiate to alveolar epithelial type I cells (AECIs).…”

Section: Introductionmentioning

confidence: 99%

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Effect of keratinocyte growth factor on growth and transdifferentiationof primary alveolar epithelial type II cells

Liu¹,

Feng²,

Tian³

et al. 2015

Turk J Med Sci

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Background/aim: To investigate the effects of keratinocyte growth factor (KGF) on the growth and transdifferentiation of primary alveolar epithelial type II cells (AECIIs). Materials and methods:The number of primary AECIIs, their viability, and cell cycle and apoptosis were studied under KGF treatment using a hemocytometer, trypan blue exclusion, and flow cytometry, respectively. Positive expressions of surfactant protein C (SP-C), aquaporin 5 (AQP5), and thyroid transcription factor 1(TTF-1) were examined with indirect immunofluorescence; mRNA levels of SP-C, AQP5, and TTF-1 were determined by polymerase chain reaction. Results:In response to KGF treatment, cell numbers were significantly increased, more cells were blocked in the S phase, and fewer cells were apoptotic or necrotic on days 2 and 4, but there was little effect on cell viability. In addition, KGF treatment resulted in higher levels of SP-C on days 2 and 8 while lowering them on day 4, higher levels of AQP5 on day 4 while lowering them on day 8, and higher levels of TTF-1 on days 2, 6, and 8. Conclusion:KGF treatment promoted proliferation of AECIIs, inhibited cell apoptosis, promoted transdifferentiation of AECIIs, and induced alveolar epithelial type I cells to revert to AECIIs.

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Section: Discussionsupporting

confidence: 69%

Section: Introductionmentioning

confidence: 99%

Effect of keratinocyte growth factor on growth and transdifferentiationof primary alveolar epithelial type II cells

Liu¹,

Feng²,

Tian³

et al. 2015

Turk J Med Sci

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“…In vivo, fibroblasts reside beneath alveolar lung epithelia and make contact with ATI and ATII cells through gaps within the basement membrane (11). Fibroblasts secrete important soluble factors (e.g., keratinocyte growth factor [KGF]) that have been reported to limit transdifferentiation and to promote ATII cell proliferation (11)(12)(13)(14)(15). ATII cells cocultured with human or rat fibroblasts or exposed to KGF exhibit surfactant mRNA expression in vitro for extended periods, suggesting that KGF (added or presumably secreted by fibroblasts) was in part responsible for retaining ATII cell differentiation in vitro (12).…”

Section: Clinical Relevancementioning

confidence: 99%

Breaking the In Vitro Alveolar Type II Cell Proliferation Barrier while Retaining Ion Transport Properties

Bove¹,

Dang²,

Cheluvaraju³

et al. 2014

Am J Respir Cell Mol Biol

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Alveolar type (AT)I and ATII cells are central to maintaining normal alveolar fluid homeostasis. When disrupted, they contribute to the pathogenesis of acute lung injury (ALI) and acute respiratory distress syndrome. Research on ATII cells has been limited by the inability to propagate primary cells in vitro to study their specific functional properties. Moreover, primary ATII cells in vitro quickly transdifferentiate into nonproliferative "ATI-like" cells under traditional culture conditions. Recent studies have demonstrated that normal and tumor cells grown in culture with a combination of fibroblast (feeder cells) and a pharmacological Rho kinase inhibitor (Y-27632) exhibit indefinite cell proliferation that resembled a "conditionally reprogrammed cell" phenotype. Using this coculture system, we found that primary human ATII cells (1) proliferated at an exponential rate, (2) established epithelial colonies expressing ATII-specific and "ATI-like" mRNA and proteins after serial passage, (3) up-regulated genes important in cell proliferation and migration, and (4) on removal of feeder cells and Rho kinase inhibitor under air-liquid interface conditions, exhibited bioelectric and volume transport characteristics similar to freshly cultured ATII cells. Collectively, our results demonstrate that this novel coculture technique breaks the in vitro ATII cell proliferation barrier while retaining cellspecific functional properties. This work will allow for a significant increase in studies designed to elucidate ATII cell function with the goal of accelerating the development of novel therapies for alveolar diseases.Keywords: proliferation; transdifferentiation; ion transport Clinical RelevanceWe describe a novel coculture technique that breaks the in vitro alveolar type II cell proliferation barrier while retaining cellspecific functional properties. This technique increases the supply of human primary alveolar type II cells and allows for additional studies to be performed focused on important biological and functional processes relevant to the physiology and pathophysiology of alveolar lung diseases.

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“…However, the cell response to injury does not completely reflect changes in intact lungs (40). Studies in clinical patients with BPD and animal models have demonstrated abnormal expression of some cytokines, such as insulin-like growth factor-I (IGF-I) (30,38), transforming growth factor (TGF)-␤1 (3,37,52), keratinocyte growth factor (KGF) (20,25), and bone morphogenetic protein (BMP) (3), which play regulatory roles in the AEC transdifferentiation process (7,10,26,44,63). These data support our hypothesis that abnormal transdifferentiation may be involved in BPD pulmonary epithelial injury.…”

mentioning

confidence: 99%

Hyperoxia stimulates the transdifferentiation of type II alveolar epithelial cells in newborn rats

Hou

Yang

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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-Supplemental oxygen treatment in preterm infants may cause bronchopulmonary dysplasia (BPD), which is characterized by alveolar simplification and vascular disorganization. Despite type II alveolar epithelial cell (AEC II) damage being reported previously, we found no decrease in the AEC II-specific marker, surfactant protein C (SP-C), in the BPD model in our previous study. We thus speculated that AEC II injury is not a unique mechanism of BPD-related pulmonary epithelial repair dysfunction and that abnormal transdifferentiation can exist. Newborn rats were randomly assigned to model (85% oxygen inhalation) and control groups (room air inhalation). Expressions of AEC I (aquaporin 5, T1␣) and AEC II markers (SP-C, SP-B) were detected at three levels: 1) in intact lung tissue, 2) in AEC II isolated from rats in the two groups, and 3) in AEC II isolated from newborn rats, which were further cultured under either hyperoxic or normoxic conditions. In the model group, increased AEC I was observed at both the tissue and cell level, and markedly increased transdifferentiation was observed by immunofluorescent double staining. Transmission electron microscopy revealed morphological changes in alveolar epithelium such as damaged AECs, a fused air-blood barrier structure, and opened tight junctions in the model group. These findings indicate that transdifferentiation of AECs is not suppressed but rather is increased under hyperoxic treatment by compensation; however, such repair during injury cannot offset pulmonary epithelial air exchange and barrier dysfunction caused by structural damage to AECs. transdifferentiation; alveolar epithelial cells; hyperoxia; bronchopulmonary dysplasia SUPPLEMENTAL OXYGEN TREATMENT, which is often necessary for preterm infants with respiratory failure, has become a major risk factor for bronchopulmonary dysplasia (BPD), one of the most common, serious complications in preterm infants (6,34). BPD is characterized by high morbidity in infants with very low birth weight (BW Ͻ 1,500 g) soon after birth and may induce multiple complications in respiratory and nervous systems during adolescence (4, 6). Despite several decades of research, the underlying pathophysiological foundation of BPD has not been completely clarified.Lung tissue consists of many different cell types, and a developmental disorder of alveolar epithelial cells (AEC) is likely a major cause of BPD (40). The alveolar area accounts for Ն99% of the internal surface area of the lungs (49). Mammals have two types of AECs that maintain normal air exchange function by mutual coordination. Type I AEC (AEC I) cover nearly 96% of alveolar spaces and closely adhere to adjacent capillaries. Such cells are the main epithelial constituents of the air-blood barrier (18, 53) and have air exchange functions. Recent studies have revealed that AEC I can also secrete transport proteins to maintain intrapulmonary fluid and electrolyte balance (9,19,22). Type II AEC (AEC II) are located at the corners of alveoli and are more abundant than AEC I bu...

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Effects of KGF on Alveolar Epithelial Cell Transdifferentiation Are Mediated by JNK Signaling

Cited by 37 publications

References 42 publications

Effect of keratinocyte growth factor on growth and transdifferentiationof primary alveolar epithelial type II cells

Effect of keratinocyte growth factor on growth and transdifferentiationof primary alveolar epithelial type II cells

Breaking the In Vitro Alveolar Type II Cell Proliferation Barrier while Retaining Ion Transport Properties

Hyperoxia stimulates the transdifferentiation of type II alveolar epithelial cells in newborn rats

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