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

Research, Anesthesiology, and Medicine Services, VA San Diego Healthcare System, San Diego; and Departments of Anesthesiology and Medicine, University of California San Diego, La Jolla, California

Address correspondence to: Randolph H. Hastings, M.D., Ph.D., VA Medical Center (125), 3350 La Jolla Village Dr., San Diego, CA 92161–5085. E-mail: rhhastings{at}ucsd.edu

Parathyroid hormone–related protein (PTHrP) promotes or suppresses apoptosis in various settings depending on cell type and context. PTHrP 1–34 and PTHrP 67–86 are type II cell growth factors with effects on pneumocyte growth and surfactant secretion. This study investigated the effects of 24 h pretreatment with these two peptides on rat type II cell apoptosis after 0.3 J/cm² ultraviolet-B irradiation. Adherent cells decreased in number by 15 ± 5% and nonadherent cells increased > 5-fold 24 h after ultraviolet irradiation. Cell loss was due predominantly to apoptosis, based on ethidium bromide exclusion, nuclear condensation, and caspase 3 activity. Nuclear condensation increased from 15.6 ± 2.2% of irradiated cells with no treatment to 25.6 ± 4.9 and 22.9 ± 1.8% of cells in ultraviolet/PTHrP 1–34 and ultraviolet/PTHrP 67–86 groups, respectively (P < 0.01), along with a 60% increase in caspase 3 activity. Effects on apoptosis were unaffected by the presence or absence of serum, but were ameliorated by growth to confluence or adherence to fibronectin. PTHrP 1–34 and PTHrP 67–86 augmented inositol phosphate levels, but had minimal effects on cAMP. Thus, PTHrP 1–34 and PTHrP 67–86 sensitize type II cells to apoptosis, possibly by a phospholipase C–dependent mechanism. The effects appear to be regulated by cell–matrix and cell–cell interactions.

Abbreviations: 7-amino-4-methyl coumarin, AMC • aspartyl-glutamyl-valyl-aspartate, DEVD • 3-[3-(Cholamidopropyl)dimethylammonio]-1-proanesulfonate, CHAPS • dimethylsulfoxide, DMSO • ethylene diamine tetraacetic acid, EDTA • ethylene Glycol-bis(beta-aminoethyl-ether)-N,N,N',N'-tetraacetatic acid, EGTA • fetal bovine serum, FBS • fluoromethylketone, fmk • human embryonic kidney, HEK • N-2-Hydroxyethylpiperazine-N'-2-ethanesulfonic acid, HEPES • high powered field, hpf • phosphate-buffered saline, PBS • piperazine-1,4-bis(2-ethanesulfonic acid), PIPES • parathyroid hormone, PTH • parathyroid hormone-related protein, PTHrP • relative fluorescent units, RFU

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