Parathyroid hormone-related protein-(38-64) regulates lung cell proliferation after silica injury.
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.
Hastings
Randolph H
RH
Research, Anesthesiology, and Medicine Services, Veterans Affairs San Diego Healthcare System, San Diego, California 92161, USA. rhhastings@ucsd.edu
Asirvatham
Angela
A
Quintana
Rick
R
Sandoval
Rebeca
R
Dutta
Ruchika
R
Burton
Douglas W
DW
Deftos
Leonard J
LJ
D000818:Animals; D002452:Cell Count; D002455:Cell Division / Q000187:drug effects; D020287:In Situ Nick-End Labeling; D008297:Male; D009929:Organ Size; D010281:Parathyroid Hormone / Q000494:pharmacology*; D044162:Parathyroid Hormone-Related Protein; D010446:Peptide Fragments / Q000494:pharmacology*; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012128:Respiratory Distress Syndrome / Q000209:etiology / Q000276:immunology / Q000473:pathology*; D016196:S Phase / Q000187:drug effects; D012822:Silicon Dioxide / Q000009:adverse effects*; D012829:Silicosis / Q000209:etiology / Q000276:immunology / Q000473:pathology*; D013936:Thymidine / Q000493:pharmacokinetics; D014316:Tritium
D010281:Parathyroid Hormone; D044162:Parathyroid Hormone-Related Protein; D010446:Peptide Fragments; C459881:parathyroid hormone-related peptide (38-64); D014316:Tritium; D012822:Silicon Dioxide; D013936:Thymidine