Amino-terminal and midmolecule parathyroid hormone-related protein, phosphatidylcholine, and type II cell proliferation in silica-injured lung.
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.
Hastings
Randolph H
RH
Research, Anesthesiology, and Medical Services, Veterans Affais San Diego Healthcare System, California 92161-5085, USA. rhhastings@ucsd.edu
Quintana
Rick A
RA
Sandoval
Rebeca
R
Burton
Douglas W
DW
Deftos
Leonard J
LJ
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001992:Bronchoalveolar Lavage Fluid; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D008171:Lung Diseases / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D008297:Male; D044162:Parathyroid Hormone-Related Protein / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D010446:Peptide Fragments / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D010713:Phosphatidylcholines / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020545:Respiratory Mucosa / Q000166:cytology / Q000378:metabolism; D012822:Silicon Dioxide; D012829:Silicosis / Q000378:metabolism* / Q000473:pathology; D013047:Specific Pathogen-Free Organisms
D000906:Antibodies; D044162:Parathyroid Hormone-Related Protein; D010446:Peptide Fragments; D010713:Phosphatidylcholines; C459881:parathyroid hormone-related peptide (38-64); C077277:parathyroid hormone-related protein (109-138); C446020:parathyroid hormone-related protein (67-86); C054296:parathyroid hormone-related protein (1-34); D012822:Silicon Dioxide