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Growth Factor Control of Type II Cell Apoptosis* FREE TO VIEW

Randolph H. Hastings, MD, PhD; D. Summers-Torres; D. Burton; L. Deftos
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*From the Veterans Affairs San Diego Health Care System, San Diego, CA.

Correspondence to: Randolph H. Hastings, MD, PhD, Anesthesia Service, Veterans Affairs Medical Center, 3350 LaJolla Village Dr, San Diego, CA 92161-5085

Chest. 1999;116(suppl_1):68S-69S. doi:10.1378/chest.116.suppl_1.68S
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We have shown that parathyroid hormone-related protein (PTHrP) is an autocrine inhibitor of type II cell proliferation and apoptosis, that its expression falls in a reproducible fashion following acute lung injury, and that decreased levels of PTHrP are necessary for type II cell proliferation (Am J Crit Care Med 155:A583). PTHrP is an autocrine inhibitor of chondrocytes and cerebellar neurons (J Cell Biol 136:205; J Biol Chem 272:14404). This study investigated whether PTHrP inhibited apoptosis in type II cells.

Adult Sprague Dawley rats (three per group) were instilled intratracheally with monoclonal antibodies 8B12 (against PTHrP 1–34), 9H7 (against PTHrP 109–141), irrelevant antibody 5E8 of the same isotype, or 8B12 with 7.5 μg PTHrP 67–86, or 9H7 with 7.5 μg PTHrP 1–34. The carrier was 1 mL phosphate-buffered saline solution with an antibody concentration of 10 μg IgG per milliliter. Lungs were removed 24 h later, fixed, and dual-stained for cytokeratin 19 as a type II cell marker and for apoptosis by terminal dUTP nick end labeling (TUNEL). Instillation of PTHrP antibodies increased the number of TUNEL-positive type II cells threefold to fivefold compared with instillation of irrelevant antibody (*p < 0.05 vs control) (Table 1 ). PTHrP 67–86 blocked the apoptosis, but PTHrP 1–34 did not. In two additional rats/antibody, type II cells were isolated by elastase digestion 24 h after instillation, stained for CD45 to exclude macrophages, and processed for DNA analysis by flow cytometry using propidium iodide. Over 10% of the type II cells from lungs instilled with PTHrP antibodies (Fig 1, left [A]) had less than a diploid (G0/G1) complement of DNA, indicating apoptosis, while <1% of cells isolated from untreated lungs (Fig 1, right [B]) were apoptotic.

In summary, reducing airspace levels of PTHrP appears to induce apoptosis of alveolar type II cells. Apoptosis is blocked by PTHrP 67–86, while proliferation of type II cells is inhibited by PTHrP 1–34 (Am J Physiol 16:L394). Thus, PTHrP peptides may regulate the size of the lung type II cell population by independent effects on both cell growth and cell death. Since PTHrP responds to lung injury, these processes may be important following acute lung injury.

Supported by Department of Veterans Affairs, NIH and NCI.

Table Graphic Jump Location
Table 1. % TUNEL-Positive Type II Cells (±SEM)

Figure Jump LinkFigure 1. DNA analysis. See text for details.Grahic Jump Location


Figure Jump LinkFigure 1. DNA analysis. See text for details.Grahic Jump Location


Table Graphic Jump Location
Table 1. % TUNEL-Positive Type II Cells (±SEM)


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