Although there is accumulated evidence of a role for Notch in the developing lung, it is still unclear how disruption of Notch signaling affects lung progenitor cell fate and differentiation events in the airway epithelium. To address this issue, we inactivated Notch signaling conditionally in the endoderm using a Shh-Cre deleter mouse line and mice carrying floxed alleles of the Pofut1 gene, which encodes an O-fucosyltransferase essential for Notch-ligand binding. We also took the same conditional approach to inactivate expression of Rbpjk, which encodes the transcriptional effector of canonical Notch signaling. Strikingly, these mutants showed an almost identical lung phenotype characterized by an absence of secretory Clara cells without evidence of cell death, and showed airways populated essentially by ciliated cells, with an increase in neuroendocrine cells. This phenotype could be further replicated in cultured wild-type lungs by disrupting Notch signaling with a gamma-secretase inhibitor. Our data suggest that Notch acts when commitment to a ciliated or non-ciliated cell fate occurs in proximal progenitors, silencing the ciliated program in the cells that will continue to expand and differentiate into secretory cells. This mechanism may be crucial to define the balance of differentiated cell profiles in different generations of the developing airways. It might also be relevant to mediate the metaplastic changes in the respiratory epithelium that occur in pathological conditions, such as asthma and chronic obstructive pulmonary disease.

Objective: To evaluate the effects of a hand hygiene program on compliance with hand hygiene and the rate of nosocomial infections in a neonatal intensive care unit (NICU).Design: Open trial.Setting: A level-III NICU in a teaching hospital.Participants: Nurses, physicians, and other healthcare workers in the NICU.Interventions: A multimodal campaign for hand hygiene promotion was conducted beginning in September 1998. This program consisted of formal lectures, written instructions and posted reminders regarding hand hygiene and proper handwashing techniques, covert observation, financial incentives, and regular group feedback on compliance. Surveillance of handwashing compliance and nosocomial infections before and during the program was analyzed.Results: Overall compliance with hand hygiene improved from 43% at baseline to 80% during the promotion program. The rate of nosocomial infections decreased from 15.13 to 10.69 per 1,000 patient-days (P = .003) with improved handwashing compliance. In particular, respiratory tract infections decreased from 3.35 to 1.06 per 1,000 patient-days during the handwashing campaign (P = .002). Furthermore, the correlation between nosocomial infection of the respiratory tract and handwashing compliance also reached statistical significance (r = -0.385; P = .014).Conclusions: Improved compliance with handwashing was associated with a significant decrease in overall rates of nosocomial infection and respiratory infections in particular. Washing hands is a simple, economical, and effective method for preventing nosocomial infections in the NICU

Pulmonary fibrosis (PF) is a major public health problem with limited therapeutic options. There is a clear need to identify novel mediators of PF to develop effective therapeutics. Here we show that an ER protein disulfide isomerase, thioredoxin domain containing 5 (TXNDC5), is highly upregulated in the lung tissues from both patients with idiopathic pulmonary fibrosis and a mouse model of bleomycin (BLM)-induced PF. Global deletion of Txndc5 markedly reduces the extent of PF and preserves lung function in mice following BLM treatment. Mechanistic investigations demonstrate that TXNDC5 promotes fibrogenesis by enhancing TGFβ1 signaling through direct binding with and stabilization of TGFBR1 in lung fibroblasts. Moreover, TGFβ1 stimulation is shown to upregulate TXNDC5 via ER stress/ATF6-dependent transcriptional control in lung fibroblasts. Inducing fibroblast-specific deletion of Txndc5 mitigates the progression of BLM-induced PF and lung function deterioration. Targeting TXNDC5, therefore, could be a novel therapeutic approach against PF.

Abnormal enlargement of the alveolar spaces is a hallmark of conditions such as chronic obstructive pulmonary disease and bronchopulmonary dysplasia. Notch signaling is crucial for differentiation and regeneration and repair of the airway epithelium. However, how Notch influences the alveolar compartment and integrates this process with airway development remains little understood. Here we report a prominent role of Notch signaling in the epithelial–mesenchymal interactions that lead to alveolar formation in the developing lung. We found that alveolar type II cells are major sites of Notch2 activation and show by Notch2-specific epithelial deletion (Notch2^cNull) a unique contribution of this receptor to alveologenesis. Epithelial Notch2 was required for type II cell induction of the PDGF-A ligand and subsequent paracrine activation of PDGF receptor-α signaling in alveolar myofibroblast progenitors. Moreover, Notch2 was crucial in maintaining the integrity of the epithelial and smooth muscle layers of the distal conducting airways. Our data suggest that epithelial Notch signaling regulates multiple aspects of postnatal development in the distal lung and may represent a potential target for intervention in pulmonary diseases. Significance Formation of the gas-exchange region of the lung occurs largely postnatally through a process called alveologenesis. Alveolar abnormalities are a hallmark of neonatal and adult chronic lung diseases. Here we report that disruption of Notch signaling in mice, particularly by Notch2, results in abnormal enlargement of the alveolar spaces reminiscent of that seen in chronic lung diseases. We provide evidence that Notch is crucial to mediate cross-talk between different cell layers, including signals such as PDGF for formation of the alveoli and maintenance of the integrity of the conducting airways.

Background: Overexpression of vascular endothelial growth factor (VEGF) correlates with vascularity, metastasis, and proliferation in colorectal cancer but the role of its homologue, placenta growth factor (PlGF), is unknown. The aim of this study was to evaluate expression and clinical implications of PlGF in colorectal cancer. Methods: We investigated 74 tumour/non-tumour pairs of colorectal cryosections. Clinical staging was based on the UICC-TNM classification. Expression levels of mRNA for PlGF and VEGF were analysed with quantitative real time reverse transcription-polymerase chain reaction. Proteins were analysed by immunohistochemical staining and enzyme linked immunoabsorbant assay. Analysis of the differences in PlGF and VEGF levels between tumour and non-tumour tissues in the same patient were performed by paired t test; differences between localised and advanced disease patients by the Mann-Whitney, χ², and Fisher’s exact tests and survival curves by the Kaplan-Meier method. Results: Expression levels for both growth factors were significantly higher in tumour than in non-tumour tissues (p⩽0.001). The ratio of PlGF expression in tumour to non-tumour in the advanced disease group was significantly higher than for the localised disease group (p = 0.009). Patients with more tumour PlGF mRNA had shorter survival (p = 0.028). The majority of PlGF was expressed in tumour cells. Conclusions: Our results suggest that PlGF expression correlates with disease progression and patient survival and may be used as a prognostic indicator for colorectal cancer.