Chronic hypoxia induces constitutive p38 mitogen-activated protein kinase activity that correlates with enhanced cellular proliferation in fibroblasts from rat pulmonary but not systemic arteries.

Pulmonary hypertension occurs commonly in patients with chronic hypoxic lung disease and is characterized by the remodeling of the pulmonary artery walls. The molecular mechanisms underlying such remodeling are unknown but we have recently shown that the stress-activated (Jnk and p38) mitogen-activated protein (MAP) kinases are activated in pulmonary artery fibroblasts following acute hypoxia. We now show that Erk and p38 MAP kinases are constitutively activated in fibroblasts derived from the remodeled pulmonary, but not the systemic circulation from rats exposed to chronically hypoxic conditions. Moreover, we find that such fibroblasts show sustained enhanced proliferative capacities relative to pulmonary artery fibroblasts derived from normoxic rats or to aortic fibroblasts from either normoxic or hypoxic rats. Finally, abrogation of p38, but not Erk MAP kinase activity by use of specific inhibitors, prevents the enhanced proliferative capacity exhibited by pulmonary artery fibroblasts. Taken together, these data suggest that enhanced p38 MAP kinase activity provides a molecular mechanism to explain the proliferation of pulmonary artery fibroblasts required for remodeling of the pulmonary vasculature.

Hypoxia enhances cellular proliferation and inositol 1,4, 5-triphosphate generation in fibroblasts from bovine pulmonary artery but not from mesenteric artery.

When pulmonary hypertension occurs in the face of hypoxia there is remodeling of all three layers of the pulmonary vessels, but in particular, there is an increase in number of adventitial fibroblasts. Hypoxia causes vasoconstriction in the pulmonary circulation and vasodilation in the systemic circulation. We hypothesized that there are fundamental differences in oxygen sensing and cell signaling between systemic and pulmonary artery cells in response to hypoxia. Here, we determined the effect of hypoxia either alone or in combination with known growth factors such as serum, endothelin-1 (ET-1), and platelet-derived growth factor (PDGF) on the proliferative responses of bovine pulmonary artery and mesenteric artery fibroblasts. Fibroblasts were obtained from primary cultures. Growth was assessed by [3H]thymidine incorporation. Inositol 1,4,5-triphosphate (IP3) generation was measured using a competitive binding assay. Hypoxia alone increased proliferation of pulmonary artery fibroblasts (611 +/- 24%), but not in those from the mesentery. Furthermore, hypoxia had the effect of increasing the replicative response of pulmonary fibroblasts to serum and PDGF, but no change was observed in the mesenteric cells. ET-1 had no effect on growth of either cell type. PDGF gave rise to a significant elevation in IP3 production under hypoxic conditions in the pulmonary artery cells (234%), but not in the mesenteric cells. ET-1 caused no change in IP3 production in any cell type. These data suggest that hypoxia sensitizes pulmonary artery fibroblasts to the proliferative effect of mitogens through a pathway that is not present, or is present but repressed, in the mesenteric cells.

Rapid rise and subsequent decline in prostate cancer incidence rates for New Mexico, 1989-1993.

Beginning in the late 1980s, a large increase in incidence rates for prostate cancer occurred in association with increased prostate-specific antigen (PSA) screening. In New Mexico, the increased screening was associated with earlier detection of cancers and decreased prostate cancer mortality, suggesting that PSA screening may be effective. PSA screening has become a controversial topic of public debate, and anecdotal reports from physicians indicated that prostate cancer screening practice patterns were changing in New Mexico. To assess whether PSA-associated trends in prostate cancer incidence were continuing, we examined incidence rates from 1989 to 1993 among men in New Mexico. From 1989 to 1992, age-adjusted rates increased substantially for non-Hispanic whites (77%), Hispanics (50%), and American Indians (27%). Although rates increased for all stages combined, incidence rates decreased for distant-stage disease, especially for non-Hispanic whites, indicating a continuing trend toward earlier detection. In 1993, incidence rates unexpectedly decreased from 203 to 158/100,000 in non-Hispanic whites, largely as a result of changes in rates in men over age 65 years. Although incidence rates decreased, the trend toward earlier detection was maintained for non-Hispanic whites. In contrast, among Hispanic and American Indians, rates did not change substantially between 1992 and 1993. Because the epidemic in prostate cancer was associated with increased PSA screening, it is likely that the trends for non-Hispanic whites are also related to PSA screening. We suggest that the decrease in rates and the continued stage shift are consistent with repeated screening of men in the population at risk.

Pediatric bicycle trauma.

Bicycle-related trauma is a serious pediatric problem. Serious injuries and even fatalities can occur, and care must be taken to avoid undertreating these patients. In an effort to further define the problem, 201 consecutive patients admitted for bicycle trauma were reviewed. The patients ranged in age from 3 to 16 years and 76% (153/201) were male. Head trauma was the most common admission diagnosis (99/201; 49%). Fourteen per cent (28/201) were admitted to the Intensive Care Unit and 23% (47/201) required an operative procedure. The average hospital stay was 3 days; however, patients who were admitted at least 24 hours after injury had an average hospital stay of 7 days.