Breaking theIn VitroAlveolar Type II Cell Proliferation Barrier while Retaining Ion Transport Properties

Inhalation of silica leads to acute lung injury and alveolar type II cell proliferation. Type II cell proliferation after hyperoxic lung injury is regulated, in part, by parathyroid hormone-related protein (PTHrP). In this study, we investigated lung PTHrP and its effects on epithelial proliferation after injury induced by silica. Lung PTHrP decreased modestly 4 days after we instilled 10 mg of silica into rat lungs and then recovered from 4 to 28 days. The number of proliferating cell nuclear antigen (PCNA)-positive type II cells was increased threefold in silica-injured lungs compared with controls. Subsequently, rats were treated with four exogenous PTHrP peptides in the silica instillate, which were administered subcutaneously daily. One peptide, PTHrP-(38–64), had consistent and significant effects on cell proliferation. PTHrP-(38–64) increased the median number of PCNA-positive cells/field nearly fourfold above controls, 380 vs. 109 ( P < 0.05). Thymidine incorporation was 2.5 times higher in type II cells isolated from rats treated with PTHrP-(38–64) compared with PBS. PTHrP-(38–64) significantly increased the number of cells expressing alkaline phosphatase, a type II cell marker. This study indicates that PTHrP-(38–64) stimulates type II cell growth and may have a role in lung repair in silica-injured rats.

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Type II cell proliferation related to migration of inflammatory cells into the lung

Experimental and Molecular Pathology ◽

10.1016/0014-4800(86)90048-1 ◽

1986 ◽

Vol 44 (3) ◽

pp. 344-352 ◽

Cited By ~ 22

Author(s):

Susan G. Shami ◽

Michael J. Evans ◽

Larry A. Martinez

Keyword(s):

Cell Proliferation ◽

Inflammatory Cells ◽

Type Ii ◽

Type Ii Cell

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Type II epithelial cells are critical target for hyperoxia-mediated impairment of postnatal lung development

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00126.2006 ◽

2006 ◽

Vol 291 (5) ◽

pp. L1101-L1111 ◽

Cited By ~ 88

Author(s):

Min Yee ◽

Peter F. Vitiello ◽

Jason M. Roper ◽

Rhonda J. Staversky ◽

Terry W. Wright ◽

...

Keyword(s):

Cell Proliferation ◽

Epithelial Cells ◽

Lung Development ◽

Type I ◽

Type Ii Cells ◽

Type Ii ◽

Newborn Mice ◽

Type I Cells ◽

Type Ii Cell ◽

I Cells

Type II epithelial cells are essential for lung development and remodeling, as they are precursors for type I cells and can produce vascular mitogens. Although type II cell proliferation takes place after hyperoxia, it is unclear why alveolar remodeling occurs normally in adults whereas it is permanently disrupted in newborns. Using a line of transgenic mice whose type II cells could be identified by their expression of enhanced green fluorescent protein and endogenous expression of surfactant proteins, we investigated the age-dependent effects of hyperoxia on type II cell proliferation and alveolar repair. In adult mice, type II cell proliferation was low during room air and hyperoxia exposure but increased during recovery in room air and then declined to control levels by day 7. Eight weeks later, type II cell number and alveolar compliance were indistinguishable from those in room air controls. In newborn mice, type II cell proliferation markedly increased between birth and postnatal day 7 before declining by postnatal day 14. Exposure to hyperoxia between postnatal days 1 and 4 inhibited type II cell proliferation, which resumed during recovery and was aberrantly elevated on postnatal day 14. Eight weeks later, recovered mice had 70% fewer type II cells and 30% increased lung compliance compared with control animals. Recovered mice also had higher levels of T1α, a protein expressed by type I cells, with minimal changes detected in genes expressed by vascular cells. These data suggest that perinatal hyperoxia adversely affects alveolar development by disrupting the proper timing of type II cell proliferation and differentiation into type I cells.

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Intratracheal administration of hepatocyte growth factor/scatter factor stimulates rat alveolar type II cell proliferation in vivo.

American Journal of Respiratory Cell and Molecular Biology ◽

10.1165/ajrcmb.15.5.8918364 ◽

1996 ◽

Vol 15 (5) ◽

pp. 574-581 ◽

Cited By ~ 53

Author(s):

R J Panos ◽

R Patel ◽

P M Bak

Keyword(s):

Cell Proliferation ◽

Growth Factor ◽

Alveolar Type ◽

Type Ii ◽

Scatter Factor ◽

Intratracheal Administration ◽

Alveolar Type Ii Cell ◽

Type Ii Cell ◽

Hepatocyte Growth

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Retinoic acid promotes primary fetal alveolar epithelial type II cell proliferation and differentiation to alveolar epithelial type I cells

In Vitro Cellular & Developmental Biology - Animal ◽

10.1007/s11626-014-9850-2 ◽

2014 ◽

Vol 51 (5) ◽

pp. 479-487 ◽

Cited By ~ 6

Author(s):

Rui-wei Gao ◽

Xiang-yong Kong ◽

Xiao-xi Zhu ◽

Guo-qing Zhu ◽

Jin-shuai Ma ◽

...

Keyword(s):

Cell Proliferation ◽

Retinoic Acid ◽

Type I ◽

Type Ii ◽

Alveolar Epithelial ◽

Type I Cells ◽

Cell Proliferation And Differentiation ◽

Proliferation And Differentiation ◽

Type Ii Cell ◽

I Cells

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30 MATERNAL NICOTINE EXPOSURE: LUNG ALVEOLAR TYPE II CELL PROLIFERATION, DIFFERENTIATION, AND METABOLIC PROFILE

Journal of Investigative Medicine ◽

10.2310/6650.2005.00005.29 ◽

2005 ◽

Vol 53 (1) ◽

pp. S83.2-S83

Author(s):

S. Sugano ◽

L. Boros ◽

Y. Wang ◽

J. Santos

Keyword(s):

Cell Proliferation ◽

Metabolic Profile ◽

Alveolar Type ◽

Nicotine Exposure ◽

Type Ii ◽

Alveolar Type Ii Cell ◽

Type Ii Cell

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Activation of HGF/c-Met signaling by ultrafine carbon particles and its contribution to alveolar type II cell proliferation

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00350.2011 ◽

2012 ◽

Vol 302 (8) ◽

pp. L755-L763 ◽

Cited By ~ 4

Author(s):

Chih-Ching Chang ◽

Jia-Jhen Chiu ◽

Shan-Ling Chen ◽

Hui-Chun Huang ◽

Hui-Fen Chiu ◽

...

Keyword(s):

Cell Proliferation ◽

Kinase Inhibitor ◽

Carbon Particle ◽

Alveolar Type ◽

Type Ii ◽

Type Ii Cell ◽

Met Phosphorylation

Hepatocyte growth factor (HGF) is a potent mitogen and motogen for various epithelial cells. The present study aimed to explore the role of HGF and c-Met receptor in ultrafine carbon particle-induced alveolar type II epithelial (type II) cell proliferation. ICR mice were intratracheally instilled with 100 μg ultrafine carbon black (ufCB) and killed at 21, 48, and 72 days postexposure to examine type II cell proliferation, HGF release, and c-Met activation. In vivo and in vitro applications of neutralizing anti-HGF antibody were used to investigate the causal role of HGF in cell proliferation. The Met kinase inhibitor SU11274 and extracellular signal-regulated kinase 1/2 (ERK1/2) inhibitor PD98059 were used to delineate the involvement of c-Met/ERK1/2 in rat L2 pulmonary epithelial cell proliferation. The results demonstrated that in vivo exposure to 100 μg ufCB caused increased HGF in bronchoalveolar lavage fluid, as well as increased HGF production, c-Met phosphorylation, and cell proliferation in type II cells. In vitro study revealed that ufCB caused a dose-dependent increase in HGF release, c-Met phosphorylation, and cell proliferation. Importantly, treatment with the neutralizing anti-HGF antibody significantly blocked ufCB-induced in vivo and in vitro type II cell proliferation. Moreover, SU11274 and PD98059 significantly reduced ufCB-increased L2 cell proliferation. Results from Western blotting demonstrated that SU11274 successfully suppressed ufCB-induced phosphorylation of c-Met and ERK1/2. In summary, the activation of HGF/c-Met signaling is a major pathway involved in ufCB-induced type II cell proliferation.

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Stimulation of net active ion transport across alveolar type II cell monolayers

AJP Cell Physiology ◽

10.1152/ajpcell.1986.250.2.c222 ◽

1986 ◽

Vol 250 (2) ◽

pp. C222-C227 ◽

Cited By ~ 44

Author(s):

G. R. Cott ◽

K. Sugahara ◽

R. J. Mason

Keyword(s):

Ion Transport ◽

Alveolar Epithelium ◽

Alveolar Type ◽

Type Ii Cells ◽

Type Ii ◽

Alveolar Type Ii Cells ◽

Cell Monolayers ◽

Alveolar Type Ii Cell ◽

Active Ion Transport ◽

Type Ii Cell

The active transcellular transport of electrolytes across the alveolar epithelium probably plays an important role in alveolar fluid homeostasis by helping to maintain the alveolus relatively free of fluid. To better understand the factors regulating active ion transport across alveolar epithelial cells, we examined the effect of a number of pharmacologically active agents on the bioelectric properties of alveolar type II cells in primary culture. Alveolar type II cells were isolated from adult male rats and cultured on collagen-coated Millipore filters for 6-14 days. The bioelectric properties of these monolayers were determined in Ussing-type chambers. The addition of 10(-3) M 8-bromoadenosine 3',5'-cyclic monophosphate (8-BrcAMP) increased the short-circuit current (Isc) from 2.9 +/- 0.75 to 6.9 +/- 0.73 microA/cm2 (means +/- SE; n = 8) and decreased the transepithelial resistance. Cholera toxin, 3-isobutyl-1-methylxanthine, and terbutaline sulfate produced similar increases in Isc and decreases in resistance. The Isc stimulated by 8-BrcAMP was Na but not Cl dependent and could be blocked by amiloride but not by furosemide. Thus 8-BrcAMP and agents that increase intracellular cAMP can stimulate a Na-dependent net active ion transport across alveolar type II cell monolayers. Similar regulatory mechanisms may be involved in controlling solute and fluid movement across the alveolar epithelium in vivo.

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