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Context.--Human papillomavirus (HPV) in the postmenopausal age group is complex, with infected patients in this age group at increased risk of progressing to invasive disease and showing decreased clearance of the virus. Additionally, atrophic changes of the cervix can make histologic distinction of high-grade squamous intraepithelial lesions (HSILs) difficult. Objective.--To determine morphologic and ancillary testing characteristics of atrophy and HSIL in postmenopausal patients. Design.--Files of patients at least 65 years of age were examined, with 81 patients (109 cases [53 benign, 56 HSIL]) included in the study. Results of morphology, immunostaining (p16 and Ki-67), and HPV RNA in situ hybridization (ISH) were noted on all cases with available material. Results.--Atrophy was present in 96 of 109 cases (88%) overall. Coarse nuclear chromatin was noted in none of the benign cases, in 19 of 30 HSIL biopsies (63%), and in 24 of 26 HSIL excisions (92%). All benign cases were negative for p16 and ISH. In the HSIL cases, 45 of 53 (89%) were positive for p16, and of cases with sufficient tissue for ISH, 44 of 45 (98%) were positive. Of the ISH/p16 discordant cases (n = 7), most were p16 negative/ISH positive (6 of 7; 86%), whereas 1 of 7 (14%) was p16 positive and ISH negative. A majority of HSIL cases showed near-fullthickness elevation of Ki-67 (45 of 54; 83%), whereas mitotic figures were less elevated. Conclusions.--In postmenopausal patients with HSIL, mitotic activity is not reliably elevated, but Ki-67 is consistently high. ISH is a more direct method of HPV detection and should be considered in cases where morphology and immunolabeling show discordance. doi: 10.5858/arpa.2021-0426-OA, Human papillomavirus (HPV) in the postmenopausal age group is complex. Not only is there a more serious risk of disease progression because of decreased clearance of virus (1) and more [...]

Alveolar epithelial apoptosis is an important feature of hyperoxia-induced lung injury in vivo and has been described in the early stages of bronchopulmonary dysplasia (chronic lung disease of preterm newborn). Molecular regulation of hyperoxia-induced alveolar epithelial cell death remains incompletely understood. In view of functional involvement of Fas/FasL system in physiological postcanalicular type II cell apoptosis, we speculated this system may also be a critical regulator of hyperoxia-induced apoptosis. The aim of this study was to investigate the effects of hyperoxia on apoptosis and apoptotic gene expression in alveolar epithelial cells. Apoptosis was studied by TUNEL, electron microscopy, DNA size analysis, and caspase assays. Fas/FasL expression was determined by Western blot analysis and RPA. We determined that in MLE-12 cells exposed to hyperoxia, caspase-mediated apoptosis was the first morphologically and biochemically recognizable mode of cell death, followed by necrosis of residual adherent cells. The apoptotic stage was associated with a threefold upregulation of Fas mRNA and protein expression and increased susceptibility to direct Fas receptor activation, concomitant with a threefold increase of FasL protein levels. Fas gene silencing by siRNAs significantly reduced hyperoxia-induced apoptosis. In murine fetal type II cells, hyperoxia similarly induced markedly increased Fas/FasL protein expression, confirming validity of results obtained in transformed MLE-12 cells. Our findings implicate the Fas/FasL system as an important regulator of hyperoxia-induced type II cell apoptosis. Elucidation of regulation of hyperoxia-induced lung apoptosis may lead to alternative therapeutic strategies for perinatal or adult pulmonary diseases characterized by dysregulated type II cell apoptosis. programmed cell death; bronchopulmonary dysplasia; chronic lung disease; oxygen; alveolar epithelial type II cell

Fas/FasL-mediated apoptosis in perinatal murine lungs. Am J Physiol Lung Cell Mol Physiol 287: L730-L742, 2004; 10.1152/ajplung.00120.2004.--Postcanalicular lung development is characterized by a time-specific increase in alveolar epithelial type II cell apoptosis. We have previously demonstrated that, in fetal rabbits, developmental type II cell apoptosis coincides with transient upregulation of the cell death regulator Fas ligand (FasL). The aims of this study were 1) to determine the spatiotemporal patterns of pulmonary apoptosis and Fas/FasL gene expression in the murine model [embryonic day 17 (E17) through postnatal day 5 (P5)], and 2) to investigate the functional involvement of the Fas/FasL system by determining the effect of Fas activation and inhibition on perinatal pulmonary apoptosis. The apoptotic activity of alveolar epithelial type II cells, determined by combined TUNEL labeling and anti-surfactant protein B immunohistochemistry, showed a dramatic increase during the perinatal transition (type II cell apoptotic index programmed cell death: lpr; CD95; lung development

Introduction/Objectives Non-albicans Candida species such as Candida parapsilosis and Candida glabrata have emerged as prevalent pathogens in premature infants. The aim of this study was to systematically delineate the histopathologic findings in neonatal non-albicans candidiasis. Methods We performed a retrospective clinicopathologic analysis of extremely premature (23–28 weeks' gestation) infants diagnosed with invasive candidiasis. Archival autopsy tissues were subjected to periodic acid-Schiff, methenamine-silver and anti-Candida (immuno)histochemical stains, as well as dual anti-Candida and anti-cytokeratin or anti-CD31 immunofluorescence assays. In addition, we studied the prevalence of intestinal Candida colonization in a consecutive autopsy series of extremely premature infants. Results Based on positive postmortem blood and/or lung cultures, invasive candidiasis (3 non-albicans and 11 Candida albicans) was diagnosed in 14 of the 187 extremely premature infants examined between 1995 and 2017. In contrast to the well-known inflammatory and tissue-destructive phenotype of congenital C. albicans infection, invasive non-albicans candidiasis/candidemia caused by C. parapsilosis and C. glabrata was inconspicuous by routine hematoxylin-eosin-based histopathologic analysis despite a heavy fungal presence detected in intestines, lungs, and blood by targeted (immuno)histochemical assays. Intestinal colonization by Candida species was identified in 16 of the 26 (61%) extremely premature neonates who had lived for at least 1 week, as assessed by anti-Candida immunostaining. Conclusion Invasive neonatal non-albicans candidiasis/candidemia appears to have no distinct histopathologic signature. Based on the notoriously low sensitivity of fungal blood cultures and the observed high frequency of Candida intestinal colonization (>50%), it is likely that non-albicans candidiasis/candidemia may be underdiagnosed in (deceased) preterm infants. Routine inclusion of targeted (immuno)histochemical fungal detection strategies in the perinatal autopsy may lead to deeper insight into the prevalence and clinical relevance of neonatal non-albicans candidiasis. [ABSTRACT FROM AUTHOR]

Recent advances in pulmonary regenerative medicine have increased the demand for alveolar epithelial progenitor cells. Fetal lung tissues from spontaneous pregnancy losses may represent a neglected, yet ethically and societally acceptable source of alveolar epithelial cells. The aim of this study was to determine the regenerative capacity of fetal lungs obtained from second trimester stillbirths. Lung tissues were harvested from 11 stillborn fetuses (13 to 22 weeks' gestation) at postdelivery intervals ranging from 10 to 41 hours and grafted to the renal subcapsular space of immune-suppressed rats to provide optimal growth conditions. Histology, epithelial and alveolar type II cell proliferation, and surfactant protein-C mRNA expression were studied in preimplantation lung tissues and in xenografts at posttransplantation week 2. All xenografts displayed advanced architectural maturation compared with their respective preimplantation tissues, regardless of gestational age and postdelivery interval. The proliferative activity of the grafts was significantly higher than that of the preimplantation tissues (mean Ki-67 labeling index 26.7%% ± 7.7%% versus 14.7%% ± 10.5%%; P < .01). The proliferative activity of grafts obtained after a long (>36 hours) postdelivery interval was significantly higher than that of the corresponding preimplantation tissue, and equivalent to that of grafts obtained after a short postdelivery interval (<14 hours). The regenerative capacity of fetal lung tissue was greater at younger (13 to 17 weeks) than at older (19 to 22 weeks) gestational ages. The presence of inflammation/chorioamnionitis did not appear to affect graft regeneration. All grafts studied displayed robust surfactant protein-C mRNA expression. In conclusion, fetal lung tissues from second trimester stillbirths can regain their inherent high regenerative potential following short-term culture, even if harvested more than 36 hours after delivery. [ABSTRACT FROM AUTHOR]

Background/purpose: Late-gestation lung remodeling is associated with alveolar type II cell apoptosis early in the saccular stage (day 28 in fetal rabbits). Intrauterine tracheal occlusion (TO), a potent stimulus of fetal lung growth and maturation, significantly increases type II cell apoptosis. The aim of this study was to determine the effect of fetal TO on the spatiotemporal expression of key apoptosis-related signaling molecules., Methods: Tracheal occlusion of fetal rabbits was performed at gestational day 25 (term, 31 days), and apoptotic gene expression was studied between days 26 and 28., Results: At days 26 and 27, the protein levels of Fas and Fas-ligand (FasL) in lung lysates were similar in TO fetuses and sham-operated controls. At day 28, however, synchronous with the onset of TO-induced pulmonary distension and type II cell apoptosis, the FasL protein content was 8-fold higher in TO lungs compared with controls (P < .01), whereas Fas levels were comparable. In contrast, Bax and Bcl-2 protein levels were similar in TO and control fetuses at all time-points. TO significantly increased the cellular concentration of immunoreactive FasL in type II cells and bronchial epithelial Clara cells. Furthermore, bronchoalveolar lavage fluid (BAL) from TO fetuses at day 28 induced significantly more type II cell apoptosis in vitro compared with control BAL, an effect that was inhibited by neutralizing anti-FasL antibody., Conclusions: Our findings show that TO results in time-specific increase of both cellular and soluble FasL in fetal lungs and implicate the Fas/FasL pathway as a pivotal autocrine and/or paracrine regulator of TO- induced type II cell apoptosis.