Placenta growth factor contributes to cell apoptosis and epithelial-to-mesenchymal transition in the hyperoxia-induced acute lung injury

Abstract Background: Bronchopulmonary dysplasia is a devastating disease of the premature newborn with high morbidity and mortality. Surfactant deficient preterm lungs are susceptible to ventilator induced lung injury, thereby developing bronchopulmonary dysplasia. Despite surfactant therapy and newer ventilation strategies, associated morbidity and mortality remains unchanged. Enhancing surfactant production and reducing ventilator induced lung injury in premature infants are critical. Recombinant keratinocyte growth factor previously been studied to treat adult respiratory distress syndrome. We hypothesized that administering recombinant human keratinocyte growth factor when initiating mechanical ventilation would help stimulate type II cell proliferation and surfactant production. Recombinant human keratinocyte growth factor may also help mitigate ventilator induced lung injury hereby reducing epithelial to mesenchymal transition, a possible precursor to later development of bronchopulmonary dysplasia. Methods: To test our hypothesis, we delivered preterm pigs via cesarean section on day 102. We performed intubation and ventilation for 24 hr. using intermittent positive pressure ventilation. After ventilation began, pigs randomly received intratracheal recombinant human keratinocyte growth factor (20 µg/kg; n=6) or sham treatment (0.5 ml 0.9% saline; n= 6). We recorded physiology data and arterial blood gases during ventilation. After 24 hr. pigs were extubated and received oxygen via nasal cannulation 12 hr. before euthanasia to collect lungs for histopathology and immunohistochemistry. Immunohistochemistry staining was graded and analyzed for surfactant protein B and epithelial to mesenchymal transition markers. Data were analyzed using t-test and Fisher’s exact test. Continuous variables analyzed using ANOVA.Results: Compared with control pigs, recombinant human keratinocyte growth factor pretreated pigs had improved ventilation with higher tidal volumes and required less oxygen (FiO2) during mechanical ventilation for similar peak pressures demonstrating improved lung compliance. Recombinant human keratinocyte growth factor pretreated pig lungs showed increased surfactant protein B expression (p< 0.05) and significantly reduced TGF-β (p< 0.05), a prominent marker for epithelial to mesenchymal transition.Conclusions: Intratracheal recombinant human keratinocyte growth factor administered at initiation of mechanical ventilation enhances surfactant production, reduce lung injury by mitigation of the changes by epithelial mesenchymal transition, thereby improving outcomes. Thus, recombinant human keratinocyte growth factor may represent a potential therapeutic strategy to prevent bronchopulmonary dysplasia.

Download Full-text

The role of placenta growth factor in the hyperoxia-induced acute lung injury in an animal model

Cell Biochemistry and Function ◽

10.1002/cbf.3085 ◽

2014 ◽

Vol 33 (1) ◽

pp. 44-49 ◽

Cited By ~ 9

Author(s):

Liang Zhang ◽

Li-Jie Yuan ◽

Shuang Zhao ◽

Yu Shan ◽

Hong-Min Wu ◽

...

Keyword(s):

Animal Model ◽

Acute Lung Injury ◽

Growth Factor ◽

Lung Injury ◽

Placenta Growth Factor

Download Full-text

Intratracheal Keratinocyte Growth Factor Enhances Surfactant Protein B Expression in Mechanically Ventilated Preterm Pigs

10.21203/rs.3.rs-112089/v1 ◽

2020 ◽

Author(s):

Ramesh Krishnan ◽

Esmond Arrindell ◽

Frank Caminita ◽

Jie Zhang ◽

Randal Buddington

Keyword(s):

Growth Factor ◽

Lung Injury ◽

Bronchopulmonary Dysplasia ◽

Epithelial To Mesenchymal Transition ◽

Keratinocyte Growth Factor ◽

Surfactant Protein ◽

Mesenchymal Transition ◽

Ventilator Induced Lung Injury ◽

Human Keratinocyte ◽

Surfactant Protein B

Abstract Background: Bronchopulmonary dysplasia is a devastating disease of the premature newborn with high morbidity and mortality. Surfactant deficient preterm lungs are susceptible to ventilator induced lung injury, thereby developing bronchopulmonary dysplasia. Despite surfactant therapy and newer ventilation strategies, associated morbidity and mortality remains unchanged. Enhancing surfactant production and reducing ventilator induced lung injury in premature infants are critical. Recombinant keratinocyte growth factor previously been studied to treat adult respiratory distress syndrome. We hypothesized that administering recombinant human keratinocyte growth factor when initiating mechanical ventilation would help stimulate type II cell proliferation and surfactant production. Recombinant human keratinocyte growth factor may also help mitigate ventilator induced lung injury hereby reducing epithelial to mesenchymal transition, a possible precursor to later development of bronchopulmonary dysplasia. Methods: To test our hypothesis, we delivered preterm pigs via cesarean section on day 102. We performed intubation and ventilation for 24 hr. using intermittent positive pressure ventilation. After ventilation began, pigs randomly received intratracheal recombinant human keratinocyte growth factor (20 μg/kg; n=6) or sham treatment (0.5 ml 0.9% saline; n= 6). We recorded physiology data and arterial blood gases during ventilation. After 24 hr. pigs were extubated and received oxygen via nasal cannulation 12 hr. before euthanasia to collect lungs for histopathology and immunohistochemistry. Immunohistochemistry staining was graded and analyzed for surfactant protein B and epithelial to mesenchymal transition markers. Data were analyzed using t-test and Fisher’s exact test. Continuous variables analyzed using ANOVA.Results: Compared with control pigs, recombinant human keratinocyte growth factor pretreated pigs had improved ventilation with higher tidal volumes and required less oxygen (FiO2) during mechanical ventilation for similar peak pressures demonstrating improved lung compliance. Recombinant human keratinocyte growth factor pretreated pig lungs showed increased surfactant protein B expression (p< 0.05) and significantly reduced TGF-β (p< 0.05), a prominent marker for epithelial to mesenchymal transition. Conclusions: Intratracheal recombinant human keratinocyte growth factor administered at initiation of mechanical ventilation enhances surfactant production, reduce lung injury by mitigation of the changes by epithelial mesenchymal transition, thereby improving outcomes. Thus, recombinant human keratinocyte growth factor may represent a potential therapeutic strategy to prevent bronchopulmonary dysplasia.

Download Full-text

Faculty Opinions recommendation of Lipocalin-2 negatively modulates the epithelial-to-mesenchymal transition in hepatocellular carcinoma through the epidermal growth factor (TGF-beta1)/Lcn2/Twist1 pathway.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718012168.793486929 ◽

2013 ◽

Author(s):

Ralf Weiskirchen ◽

Jens Herrmann

Keyword(s):

Hepatocellular Carcinoma ◽

Growth Factor ◽

Epidermal Growth Factor ◽

Epithelial To Mesenchymal Transition ◽

Lipocalin 2 ◽

Mesenchymal Transition ◽

Epidermal Growth

Download Full-text

Roles of microRNAs in Regulating Cancer Stemness in Head and Neck Cancers

Cancers ◽

10.3390/cancers13071742 ◽

2021 ◽

Vol 13 (7) ◽

pp. 1742

Author(s):

Melysa Fitriana ◽

Wei-Lun Hwang ◽

Pak-Yue Chan ◽

Tai-Yuan Hsueh ◽

Tsai-Tsen Liao

Keyword(s):

Growth Factor ◽

Head And Neck ◽

Cancer Cells ◽

Signaling Pathways ◽

Epithelial To Mesenchymal Transition ◽

Survival Rates ◽

Growth Factor Receptor ◽

Cancer Stemness ◽

Mesenchymal Transition

Head and neck squamous cell carcinomas (HNSCCs) are epithelial malignancies with 5-year overall survival rates of approximately 40–50%. Emerging evidence indicates that a small population of cells in HNSCC patients, named cancer stem cells (CSCs), play vital roles in the processes of tumor initiation, progression, metastasis, immune evasion, chemo-/radioresistance, and recurrence. The acquisition of stem-like properties of cancer cells further provides cellular plasticity for stress adaptation and contributes to therapeutic resistance, resulting in a worse clinical outcome. Thus, targeting cancer stemness is fundamental for cancer treatment. MicroRNAs (miRNAs) are known to regulate stem cell features in the development and tissue regeneration through a miRNA–target interactive network. In HNSCCs, miRNAs act as tumor suppressors and/or oncogenes to modulate cancer stemness and therapeutic efficacy by regulating the CSC-specific tumor microenvironment (TME) and signaling pathways, such as epithelial-to-mesenchymal transition (EMT), Wnt/β-catenin signaling, and epidermal growth factor receptor (EGFR) or insulin-like growth factor 1 receptor (IGF1R) signaling pathways. Owing to a deeper understanding of disease-relevant miRNAs and advances in in vivo delivery systems, the administration of miRNA-based therapeutics is feasible and safe in humans, with encouraging efficacy results in early-phase clinical trials. In this review, we summarize the present findings to better understand the mechanical actions of miRNAs in maintaining CSCs and acquiring the stem-like features of cancer cells during HNSCC pathogenesis.

Download Full-text

Endothelial-to-mesenchymal transition in lipopolysaccharide-induced acute lung injury drives a progenitor cell-like phenotype

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00074.2016 ◽

2016 ◽

Vol 310 (11) ◽

pp. L1185-L1198 ◽

Cited By ~ 12

Author(s):

Toshio Suzuki ◽

Yuji Tada ◽

Rintaro Nishimura ◽

Takeshi Kawasaki ◽

Ayumi Sekine ◽

...

Keyword(s):

Bone Marrow ◽

Endothelial Cells ◽

Acute Lung Injury ◽

Lung Injury ◽

Vascular Endothelial Cells ◽

Repair Process ◽

Vascular Endothelial ◽

Mesenchymal Transition ◽

Oxidase Inhibition ◽

Endothelial To Mesenchymal Transition

Pulmonary vascular endothelial function may be impaired by oxidative stress in endotoxemia-derived acute lung injury. Growing evidence suggests that endothelial-to-mesenchymal transition (EndMT) could play a pivotal role in various respiratory diseases; however, it remains unclear whether EndMT participates in the injury/repair process of septic acute lung injury. Here, we analyzed lipopolysaccharide (LPS)-treated mice whose total number of pulmonary vascular endothelial cells (PVECs) transiently decreased after production of reactive oxygen species (ROS), while the population of EndMT-PVECs significantly increased. NAD(P)H oxidase inhibition suppressed EndMT of PVECs. Most EndMT-PVECs derived from tissue-resident cells, not from bone marrow, as assessed by mice with chimeric bone marrow. Bromodeoxyuridine-incorporation assays revealed higher proliferation of capillary EndMT-PVECs. In addition, EndMT-PVECs strongly expressed c- kit and CD133. LPS loading to human lung microvascular endothelial cells (HMVEC-Ls) induced reversible EndMT, as evidenced by phenotypic recovery observed after removal of LPS. LPS-induced EndMT-HMVEC-Ls had increased vasculogenic ability, aldehyde dehydrogenase activity, and expression of drug resistance genes, which are also fundamental properties of progenitor cells. Taken together, our results demonstrate that LPS induces EndMT of tissue-resident PVECs during the early phase of acute lung injury, partly mediated by ROS, contributing to increased proliferation of PVECs.

Download Full-text

Long non-coding RNA OIP5-AS1 aggravates acute lung injury by promoting inflammation and cell apoptosis via regulating the miR-26a-5p/TLR4 axis

BMC Pulmonary Medicine ◽

10.1186/s12890-021-01589-1 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Qingsong Sun ◽

Man Luo ◽

Zhiwei Gao ◽

Xiang Han ◽

Weiqin Wu ◽

...

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Inflammatory Response ◽

Cell Apoptosis ◽

Quantitative Polymerase Chain Reaction ◽

Luciferase Reporter ◽

Enzyme Linked Immunosorbent Assay ◽

Interacting Protein ◽

Wide Range

Abstract Background Acute lung injury (ALI) is a pulmonary disorder that leads to acute respiration failure and thereby results in a high mortality worldwide. Increasing studies have indicated that toll-like receptor 4 (TLR4) is a promoter in ALI, and we aimed to explore the underlying upstream mechanism of TLR4 in ALI. Methods We used lipopolysaccharide (LPS) to induce an acute inflammatory response in vitro model and a murine mouse model. A wide range of experiments including reverse transcription quantitative polymerase chain reaction, western blot, enzyme linked immunosorbent assay, flow cytometry, hematoxylin–eosin staining, RNA immunoprecipitation, luciferase activity and caspase-3 activity detection assays were conducted to figure out the expression status, specific role and potential upstream mechanism of TLR4 in ALI. Result TLR4 expression was upregulated in ALI mice and LPS-treated primary bronchial/tracheal epithelial cells. Moreover, miR-26a-5p was confirmed to target TLR4 according to results of luciferase reporter assay. In addition, miR-26a-5p overexpression decreased the contents of proinflammatory factors and inhibited cell apoptosis, while upregulation of TLR4 reversed these effects of miR-26a-5p mimics, implying that miR-26a-5p alleviated ALI by regulating TLR4. Afterwards, OPA interacting protein 5 antisense RNA 1 (OIP5-AS1) was identified to bind with miR-26a-5p. Functionally, OIP5-AS1 upregulation promoted the inflammation and miR-26a-5p overexpression counteracted the influence of OIP5-AS1 upregulation on cell inflammatory response and apoptosis. Conclusion OIP5-AS1 promotes ALI by regulating the miR-26a-5p/TLR4 axis in ALI mice and LPS-treated cells, which indicates a promising insight into diagnostics and therapeutics in ALI.

Download Full-text