Proapoptotic Effects of Parathyroid Hormone-Related Protein in Type II Pneumocytes

2003 ◽  
Vol 29 (6) ◽  
pp. 733-742 ◽  
Author(s):  
Randolph H. Hastings ◽  
Rick A. Quintana ◽  
Rebeca Sandoval ◽  
Devin Duey ◽  
Yvette Rascon ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Type Ii ◽  
Related Protein ◽  
Parathyroid Hormone Related Protein ◽  
Type Ii Pneumocytes

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.

Parathyroid hormone-related protein (PTHrP) action in rat articular chondrocytes: comparison of PTH(1–34), PTHrP(1–34), PTHrP(1–141), PTHrP(100–114) and antisense oligonucleotides against PTHrP

1996 ◽  
Vol 150 (3) ◽  
pp. 359-368 ◽  
Author(s):  
T Tsukazaki ◽  
A Ohtsuru ◽  
H Namba ◽  
J Oda ◽  
K Motomura ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Dna Synthesis ◽  
Antisense Oligonucleotides ◽  
Articular Chondrocytes ◽  
Type Ii Collagen ◽  
Type Ii ◽  
Related Protein ◽  
Collagen Mrna ◽  
Parathyroid Hormone Related Protein ◽  
Significant Difference

Abstract Parathyroid hormone-related protein (PTHrP) is thought to be an important autocrine/paracrine factor for chondrocyte metabolism since mice lacking the PTHrP gene exhibit abnormal cartilage development. To determine the biological role of PTHrP in chondrocytes, we first compared the agonist potency of human (h) PTHrP(1–34) with hPTH(1–34) in cultured rat articular chondrocytes. Neither hPTHrP(1–34) nor hPTH(1–34) altered basal DNA synthesis, but attenuated the stimulatory effect of transforming growth factor β (TGF-β). Both agents suppressed the expression of α(1) type II collagen mRNA in a dose–response fashion with the same potency. In addition, the action of exogenously added hPTHrP(1–34) and hPTH(1–34) on intracellular cAMP and [Ca2+]i levels was similar. We next compared the effect of PTHrP within its entire amino acid sequence (1–141). With regard to thymidine incorporation, α(1) type II collagen gene expression and accumulation of cAMP and [Ca2+]i level, there was no significant difference between hPTHrP(1–34) and hPTHrP(1–141). PTHrP C-terminal (100–114) did not show any function. To further investigate PTHrP function, intracellular PTHrP translation was inhibited by a transgene of antisense oligonucleotides against PTHrP. Antisense oligonucleotides decreased PTHrP mRNA translation, specifically inhibited DNA synthesis in control as well as TGF-β-treated chondrocytes and enhanced α(1) type II collagen mRNA expression in TGF-β-treated chondrocytes. These results suggest that there is no significant difference between exogenously added hPTH(1–34), hPTHrP(1–34) and PTHrP(1–141) with regard to the biological action of these agents, including cell growth, differentiation and second messenger pathway. However, the result of DNA synthesis in the antisense PTHrP-inhibition study suggests that intracellular PTHrP may have an as yet unknown biological role, in addition to a classical PTH/PTHrP receptor-mediated function in the rat articular chondrocyte. Journal of Endocrinology (1996) 150, 359–368

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.

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