Parathyroid hormone-related protein-(38–64) regulates lung cell proliferation after silica injury

2002 ◽  
Vol 283 (1) ◽  
pp. L12-L21 ◽  
Author(s):  
Randolph H. Hastings ◽  
Angela Asirvatham ◽  
Rick Quintana ◽  
Rebeca Sandoval ◽  
Ruchika Dutta ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Parathyroid Hormone ◽  
Lung Injury ◽  
Nuclear Antigen ◽  
Alveolar Type ◽  
Type Ii Cells ◽  
Type Ii ◽  
Related Protein ◽  
Parathyroid Hormone Related Protein ◽  
Type Ii Cell

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.

Parathyroid hormone-related protein response to hyperoxic lung injury

2002 ◽  
Vol 282 (6) ◽  
pp. L1198-L1208 ◽  
Author(s):  
Randolph H. Hastings ◽  
Rita M. Ryan ◽  
Carl T. D'Angio ◽  
Bruce A. Holm ◽  
Alka Patel ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Parathyroid Hormone ◽  
Lung Injury ◽  
Growth Inhibitor ◽  
Alveolar Type ◽  
Type Ii ◽  
Related Protein ◽  
Adult Rats ◽  
Parathyroid Hormone Related Protein ◽  
Type Ii Cell

Parathyroid hormone-related protein (PTHrP) is a growth inhibitor for alveolar type II cells. Type II cell proliferation after lung injury from 85% oxygen is regulated, in part, by a fall in lung PTHrP. In this study, we investigated lung PTHrP after injury induced by >95% oxygen in rats and rabbits. In adult rats, lung PTHrP rose 10-fold over controls to 6,356 ± 710 pg/ml (mean ± SE) at 48 h of hyperoxia. Levels fell to 299 ± 78 pg/ml, and staining for PTHrP mRNA was greatly reduced at 60 h ( P < 0.05), the point of most severe injury and greatest pneumocyte proliferation. In adult rabbits, lung PTHrP peaked at 3,289 ± 230 pg/ml after 64 h of hyperoxia with 24 h of normoxic recovery and then dropped to 1,629 ± 153 pg/ml at 48 h of recovery ( P < 0.05). Type II cell proliferation peaked shortly after the fall in PTHrP. In newborn rabbits, lavage PTHrP increased by 50% during the first 8 days of hyperoxia, whereas type II cell growth decreased. PTHrP declined at the LD50, concurrent with increased type II cell division. In summary, lung PTHrP initially rises after injury with >95% hyperoxia and then falls near the peak of injury. Changes in PTHrP are temporally related to type II cell proliferation and may regulate repair of lung injury.

Amino-terminal and midmolecule parathyroid hormone-related protein, phosphatidylcholine, and type II cell proliferation in silica-injured lung

2003 ◽  
Vol 285 (6) ◽  
pp. L1312-L1322 ◽  
Author(s):  
Randolph H. Hastings ◽  
Rick A. Quintana ◽  
Rebeca Sandoval ◽  
Douglas W. Burton ◽  
Leonard J. Deftos
Keyword(s):  
Cell Proliferation ◽  
Parathyroid Hormone ◽  
Lung Injury ◽  
Significant Inhibition ◽  
Regulatory Role ◽  
Type Ii ◽  
Related Protein ◽  
Amino Terminal ◽  
Parathyroid Hormone Related Protein ◽  
Type Ii Cell

Acute silica lung injury is marked by alveolar phospholipidosis and type II cell proliferation. Parathyroid hormone-related protein (PTHrP) 1-34 could have a regulatory role in this process because it stimulates phosphatidylcholine secretion and inhibits type II cell growth. Other regions of the PTHrP molecule may have biological activity and can also exert pulmonary effects. This study examined the temporal pattern for expression of several regions of PTHrP after silica lung injury and evaluated the effects of changes in expression on cell proliferation and lung phospholipids. Expression of all PTHrP regions fell at 4 days after injury. Reversing the decline in PTHrP 1-34 or PTHrP 67-86 with one intratracheal dose and four daily subcutaneous doses of PTHrP 1-34 or PTHrP 67-86 stimulated bronchoalveolar lavage disaturated phosphatidylcholine (DSPC) levels. Cell culture studies indicate that the peptides exerted direct effects on DSPC secretion by type II cells. Neither peptide affected type II cell proliferation with this dosing regimen, but addition of an additional intratracheal dose resulted in significant inhibition of growth, consistent with previous effects of PTHrP 1-34 in hyperoxic lung injury. These studies establish a regulatory role for PTHrP 1-34 and PTHrP 67-86 in DSPC metabolism and type II cell proliferation in silica injury. Growth inhibitory effects of PTHrP could interact with phospholipid stimulation by affecting type II cell numbers. Further studies are needed to explore the complex interactions of PTHrP-derived peptides and the type II cell response at various stages of silica lung injury.

Parathyroid hormone-related protein, an autocrine growth inhibitor of alveolar type II cells

1997 ◽  
Vol 272 (3) ◽  
pp. L394-L399 ◽  
Author(s):  
R. H. Hastings ◽  
D. Summers-Torres ◽  
B. Yaszay ◽  
J. LeSueur ◽  
D. W. Burton ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Cultured Cells ◽  
Nuclear Antigen ◽  
Cytokeratin 19 ◽  
Alveolar Type ◽  
Type Ii Cells ◽  
Type Ii ◽  
Related Protein ◽  
Alveolar Cells ◽  
Parathyroid Hormone Related Protein

Parathyroid hormone-related protein (PTHRP) is an autocrine regulator of differentiation for type II pneumocytes [R. H. Hastings, D. Summers-Torres, T. C. Cheung, L. S. Ditmer, D. W. Burton, E. M. Petrin, R. G. Spragg, J. Li, and L. J. Deftos. Am. J. Physiol. 270 (Lung Cell. Mol. Physiol. 14): L353-L361, 1996]. We investigated autocrine effects on growth by decreasing endogenous PTHRP in rat type II cells. Cultured cells were incubated with antibodies against PTHRP-(1-34) (8B12) or PTHRP-(109-141) (9H7) or an irrelevant antibody (1 microg/ml) for 3 days. Conditioned media from the irrelevant antibody group contained 143 +/- 8 fg PTHRP/ 100,000 cells. The 8B12 and 9H7 reduced levels to 45 +/- 8 and 88 +/- 16 fg PTHRP/100,000 cells, respectively (n = 4 cell isolations, P < 0.05). Cells treated with the PTHRP antibodies nearly tripled in number. The irrelevant antibody had no effect on growth. Exogenous PTHRP-(1-34) (2.5 nM) blocked the growth-stimulating effect of 9H7. Instilled intratracheal 8B12 and 9H7 induced expression of proliferating cell nuclear antigen in clusters of alveolar cells in rats. Clustered cells expressed surfactant apoproteins and cytokeratin 19. These data suggest that endogenous PTHRP-(1-34) inhibits proliferation of type II cells in vivo and in vitro.

Hyperoxia increases keratinocyte growth factor mRNA expression in neonatal rabbit lung

1999 ◽  
Vol 276 (1) ◽  
pp. L105-L113 ◽  
Author(s):  
Lama Charafeddine ◽  
Carl T. D’Angio ◽  
Julie L. Richards ◽  
Barry R. Stripp ◽  
Jacob N. Finkelstein ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Lung Injury ◽  
Mrna Expression ◽  
Keratinocyte Growth Factor ◽  
Nuclear Antigen ◽  
Type Ii ◽  
Alveolar Epithelial ◽  
Hyperoxic Lung Injury ◽  
Type Ii Cell ◽  
Proliferating Cell

Acute hyperoxic lung injury remains a major factor in the development of chronic lung disease in neonates. A critical step in the repair of acute lung injury is the proliferation of type II alveolar epithelial cells. Type II cell proliferation is stimulated by keratinocyte growth factor (KGF), an epithelial cell-specific mitogen. We sought to investigate KGF mRNA expression in relation to type II cell proliferation during hyperoxic lung injury. We studied a previously described newborn (NB) rabbit model of acute and chronic hyperoxic injury [C. T. D’Angio, J. N. Finkelstein, M. B. LoMonaco, A. Paxhia, S. A. Wright, R. B. Baggs, R. H. Notter, and R. M. Ryan. Am. J. Physiol. 272 ( Lung Cell. Mol. Physiol. 16): L720–L730, 1997]. NB rabbits were placed in 100% O2 for 9 days and then recovered in 60% O2. RT-PCR was used to synthesize and amplify a 267-bp fragment of rabbit KGF cDNA from whole lung RNA. KGF mRNA expression was analyzed by ribonuclease protection assay, and mRNA abundance was quantified by phosphorimaging. Proliferating cell nuclear antigen immunohistochemistry was used on lung sections to identify proliferating cells. The rabbit partial cDNA sequenced was >95% homologous to human cDNA, and all amino acids were conserved. Whole lung KGF mRNA expression was increased 12-fold after 6 days of hyperoxia compared with control lungs, and remained increased throughout the 100% O2 exposure period. Proliferating cell nuclear antigen immunohistochemistry showed an increase in type II cell proliferation after 8–12 days of hyperoxia. NB rabbits exposed to hyperoxic injury exhibit increased whole lung KGF mRNA expression preceding type II cell proliferation. KGF may be an important mitogen in the regulation of alveolar epithelial repair after hyperoxic lung injury.

Parathyroid hormone-related protein reduces alveolar epithelial cell proliferation during lung injury in rats

2000 ◽  
Vol 279 (1) ◽  
pp. L194-L200 ◽  
Author(s):  
Randolph H. Hastings ◽  
John T. Berg ◽  
Daphne Summers-Torres ◽  
Douglas W. Burton ◽  
Leonard J. Deftos
Keyword(s):  
Cell Proliferation ◽  
Parathyroid Hormone ◽  
Lung Injury ◽  
Alveolar Epithelial Cell ◽  
Epithelial Cell Proliferation ◽  
Related Protein ◽  
High Power Field ◽  
Alveolar Epithelial ◽  
Parathyroid Hormone Related Protein ◽  
Pthrp Expression

Parathyroid hormone-related protein (PTHrP) is a growth inhibitor for alveolar type II cells and could be a regulatory factor for alveolar epithelial cell proliferation after lung injury. We investigated lung PTHrP expression in rats exposed to 85% oxygen. Lung levels of PTHrP were significantly decreased between 4 and 8 days of hyperoxia, concurrent with increased expression of proliferating cell nuclear antigen and increased incorporation of 5-bromo-2′-deoxyuridine (BrdU) into DNA in lung corner cells. PTHrP receptor was present in both normal and hyperoxic lung. To test whether the fall in PTHrP was related to cell proliferation, we instilled PTHrP into lungs on the fourth day of hyperoxia. Eight hours later, BrdU labeling in alveolar corner cells was 3.2 ± 0.4 cells/high-power field in hyperoxic PBS-instilled rats compared with 0.5 ± 0.3 cells/high-power field in PTHrP-instilled rats ( P < 0.01). Thus PTHrP expression changes in response to lung injury due to 85% oxygen and may regulate cell proliferation.

Sulfation of extracellular matrices modifies responses of alveolar type II cells to fibroblast growth factors

1996 ◽  
Vol 271 (5) ◽  
pp. L688-L697 ◽  
Author(s):  
P. L. Sannes ◽  
J. Khosla ◽  
P. W. Cheng
Keyword(s):  
Growth Factors ◽  
Biological Significance ◽  
Alveolar Type ◽  
Type I ◽  
Type Ii Cells ◽  
Type Ii ◽  
Fibroblast Growth ◽  
Alveolar Type Ii Cells ◽  
Proliferation And Differentiation ◽  
Type Ii Cell

The pulmonary alveolar basement membrane (BM) associated with alveolar type II cells has been shown to be significantly less sulfated than that of type I cells. To examine the biological significance of this observation, we measured the incorporation of 5-bromodeoxyuridine (BrdU) as an indicator of DNA synthesis in isolated rat type II cells cultured for 72-120 h on substrata that were naturally sulfated, not sulfated, or chemically desulfated in serum-free, hormonally defined media, with and without selected growth factors. The percentage of cells incorporating BrdU was significantly elevated by desulfated chondroitin sulfate in the presence of fibroblast growth factor-2 (FGF-2 or basic FGF) and depressed by heparin in the presence of either FGF-1 or acidic FGF or FGF-2. This depressive effect was lost by removing sulfate from the heparin. Some responses were dependent on the period of time in culture and concentration and molecular weight of the substrata. These observations support the notion that sulfation per se of certain components of BM is a key determinant of type II cell responses to select growth factors that may define patterns of proliferation and differentiation.

Parathyroid Hormone-Related Protein in Epithelial Lining Fluid in Humans Negatively Correlates With the Severity of Lung Injury

CHEST Journal ◽  
2002 ◽  
Vol 121 (3) ◽  
pp. 852-857 ◽  
Author(s):  
Jean-Baptiste Stern ◽  
Oana Bernard ◽  
Catherine Paugam ◽  
Caroline Silve ◽  
Jean Mantz ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Lung Injury ◽  
Epithelial Lining ◽  
Related Protein ◽  
Epithelial Lining Fluid ◽  
Parathyroid Hormone Related Protein

Nitric oxide alters metabolism in isolated alveolar type II cells

1996 ◽  
Vol 271 (1) ◽  
pp. L23-L30 ◽  
Author(s):  
P. R. Miles ◽  
L. Bowman ◽  
L. Huffman
Keyword(s):  
Nitric Oxide ◽  
Oxygen Consumption ◽  
Atp Synthesis ◽  
Alveolar Type ◽  
Type Ii Cells ◽  
Type Ii ◽  
Atp Content ◽  
Alveolar Type Ii Cells ◽  
Type Ii Cell ◽  
Cellular Oxygen

Alveolar type II cells may be exposed to nitric oxide (.NO) from external sources, and these cells can also generate .NO. Therefore we studied the effects of altering .NO levels on various type II cell metabolic processes. Incubation of cells with the .NO generator, S-nitroso-N-acetylpenicillamine (SNAP; 1 mM), leads to reductions of 60-70% in the synthesis of disaturated phosphatidylcholines (DSPC) and cell ATP levels. Cellular oxygen consumption, an indirect measure of cell ATP synthesis, is also reduced by SNAP. There is no direct effect of SNAP on lung mitochondrial ATP synthesis, suggesting that .NO does not directly inhibit this process. On the other hand, incubation of cells with NG-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthase (NOS), the enzyme responsible for .NO synthesis, results in increases in DSPC synthesis, cell ATP content, and cellular oxygen consumption. The L-NAME effects are reversed by addition of L-arginine, the substrate for NOS. Production of .NO by type II cells is inhibited by L-NAME, a better inhibitor of constitutive NOS (cNOS) than inducible NOS (iNOS), and is reduced in the absence of external calcium. Aminoguanidine, a specific inhibitor of iNOS, has no effect on cell ATP content or on .NO production. These results indicate that alveolar type II cell lipid and energy metabolism can be affected by .NO and suggest that there may be cNOS activity in these cells.

Enhanced alveolar type II cell growth on a pulmonary extracellular matrix over fibroblasts

1997 ◽  
Vol 272 (3) ◽  
pp. L413-L417 ◽  
Author(s):  
I. Y. Adamson ◽  
L. Young ◽  
J. Bakowska
Keyword(s):  
Extracellular Matrix ◽  
Cell Growth ◽  
Growth Effect ◽  
Lung Fibroblasts ◽  
Cell Contact ◽  
Alveolar Type ◽  
Thymidine Uptake ◽  
Type Ii Cells ◽  
Type Ii ◽  
Type Ii Cell

The growth of alveolar type II cells was studied when these cells were maintained for 2 days on a pulmonary endothelium-derived extracellular matrix (ECM) on a filter with or without lung fibroblasts in the lower chambers of culture wells. Type II cell proliferation was enhanced by the ECM compared with other substrates but was significantly higher with fibroblasts beneath. This was determined by thymidine uptake and cell numbers. The diffusing factor from fibroblasts appeared to be keratinocyte growth factor (KGF), because this cytokine increased type II cell growth in culture and the neutralizing antibody to KGF blocked the observed fibroblast-induced growth increase. None of the antibodies to various cytokines had any effect on the ECM-induced proliferation. Although the type II cells were shown to produce degradative activity for the ECM, there was little secreted enzyme activity in supernatants and there was no demonstrated autocrine-regulated growth effect. The results suggest that type II cell growth may be stimulated by both 1) a matrix-bound factor that acts through a cell contact-mediated process, and 2) a fibroblast-secreted factor that appears to be KGF.

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