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The alveolar type II epithelial cells (AEC2s) act as stem cells in the lung for alveolar epithelial maintenance and repair. Chemokine C-X-C motif chemokine 10 (CXCL10) is expressed in injured tissues, modulating multiple cellular functions. AEC2s, previously reported to release chemokines to recruit leukocytes, were found in our study to secrete CXCL10 after bleomycin injury. We found that Sftpc-Cxcl10 transgenic mice were protected from bleomycin injury. The transgenic mice showed an increase in the AEC2 population in the lung by flow cytometry analysis. Both endogenous and exogenous CXCL10 promoted the colony formation efficiency of AEC2s in a three-dimensional (3-D) organoid growth assay. We identified that the regenerative effect of CXCL10 was CXCR3 independent using Cxcr3-deficient mice, but it was related to the TrkA pathway. Binding experiments showed that CXCL10 interacted with TrkA directly and reversibly. This study demonstrates a previously unidentified AEC2 autocrine signaling of CXCL10 to promote their regeneration and proliferation, probably involving a CXCR3-independent TrkA pathway. NEW & NOTEWORTHY: CXCL10 may aid in lung injury recovery by promoting the proliferation of alveolar stem cells and using a distinct regulatory pathway from the classical one. [ABSTRACT FROM AUTHOR]

Introduction: Adipose-derived stem cells (ADSCs) have been subject of several studies due to their abundance, ease of preparation, and application in bone regeneration. We aim to compare effectiveness of alveolar reconstruction utilizing human cancellous freeze-dried graft (HCG) and beta tricalcium phosphate (BTP), both seeded with human ADSC (hADSC) and autologous bone graft (ABG). Material and Methods: A 5 × 5 mm alveolar defect in 36 male Wistar rats were treated using: ABG (C), HCG–hADSC (H1), and BTP–hADSC (H2). At 1 and 8 weeks after surgery, runt-related transcription factor 2 (RUNX2), alkaline phosphatase (ALP), osterix (OSX), and bone morphogenetic protein 2 (BMP2; g/mL) were quantified using immunohistochemistry, while bone tissue volume (BV, mm3), bone tissue volume fraction (BF, percentage), and trabecular thickness of bone (TT, mm) were assessed using micro-computed tomography (CT). Results: One week after surgery, H2 was higher in RUNX2, OSX, ALP, and BMP2 than C (P <.05). Only RUNX2 and OSX were found to be higher in H1 than C, while ALP and BMP2 were higher in H2 than H1. Micro-CT revealed that H2 had a higher TT than C and C had a higher TT than H1 (P <.05). Eight weeks after surgery, both H2 and H1 was higher in RUNX2, OSX, ALP, and BMP2 than C (P <.05). RUNX2 and BMP2 were found to be higher in H1 than H2. Micro-CT revealed that H2 had higher BV and TT than C and H1 (P <.05). Conclusions: Exogenous hADSC strengthened the effectiveness of HCG and BTP to accelerate osteogenesis, osteoconduction, and osteoinduction. The latter was the most successful in bone formation, followed by HCG and ABG. [ABSTRACT FROM AUTHOR]

Statins have demonstrated positive results in alveolar repair after induced osteoporosis in humans and rats. This study aimed to evaluate the osteogenic potential of rosuvastatin (RSV) solution associated with collagen sponge in post-extraction rat alveoli. An experimental study was carried out at the Fluminense Federal University in 30 Wistar rats (female) randomly distributed into three experimental groups: group I—dental sockets filled with a blood clot (CS); group II—dental sockets filled with collagen sponge (EC); and group III—collagen sponge associated with RSV. Slides stained with hematoxylin and eosin (HE) were used for histomorphometric analysis to evaluate newly formed bone, connective tissue, and biomaterial in the respective groups, comparing them over different periods (7 and 42 days). The Shapiro–Wilk test was used to evaluate the same experimental period, and the Mann–Whitney test was used to compare the different periods between the groups. At 7 days, the clot group showed greater new bone formation (median 23.27; IQR 10.62–4.74) than the sponge group (median 2.25; IQR 3.42–1.53) and RSV group (median 0; IQR 0–0; p = 0.03), respectively. At 42 days, the clot group (median 63.90; IQR 7.54–3.73) showed better results regarding newly formed bone compared to the RSV group (median 26.33; IQR 4.78–2.24; p = 0.003). The present study demonstrated no advantages in the use of RSV in relation to the control group and no statistical difference between groups II and III. [ABSTRACT FROM AUTHOR]

Statins have demonstrated positive results in alveolar repair after induced osteoporosis in humans and rats. This study aimed to evaluate the osteogenic potential of rosuvastatin (RSV) solution associated with collagen sponge in post-extraction rat alveoli. An experimental study was carried out at the Fluminense Federal University in 30 Wistar rats (female) randomly distributed into three experimental groups: group I—dental sockets filled with a blood clot (CS); group II—dental sockets filled with collagen sponge (EC); and group III—collagen sponge associated with RSV. Slides stained with hematoxylin and eosin (HE) were used for histomorphometric analysis to evaluate newly formed bone, connective tissue, and biomaterial in the respective groups, comparing them over different periods (7 and 42 days). The Shapiro–Wilk test was used to evaluate the same experimental period, and the Mann–Whitney test was used to compare the different periods between the groups. At 7 days, the clot group showed greater new bone formation (median 23.27; IQR 10.62–4.74) than the sponge group (median 2.25; IQR 3.42–1.53) and RSV group (median 0; IQR 0–0; p = 0.03), respectively. At 42 days, the clot group (median 63.90; IQR 7.54–3.73) showed better results regarding newly formed bone compared to the RSV group (median 26.33; IQR 4.78–2.24; p = 0.003). The present study demonstrated no advantages in the use of RSV in relation to the control group and no statistical difference between groups II and III.

Pulmonary fibrosis is characterized by loss of normal alveoli, accumulation of pathologic activated fibroblasts, and exuberant extracellular matrix deposition that over time can lead to progressive loss of respiratory function and death. This loss of respiratory function is associated with the loss of alveolar type 1 cells (AT1) that play a crucial role in gas exchange and the depletion of the alveolar type 2 cells (AT2) that act as progenitor cells to regenerate the AT1 and AT2 cell populations during repair. Understanding the mechanisms that regulate normal alveolar repair and those associated with pathologic repair is essential to identify potential therapeutic targets to treat or delay progression of fibrotic diseases. The Hippo/YAP developmental signaling pathway has been implicated as a regulator of normal alveolar development and repair. In idiopathic pulmonary fibrosis, aberrant activation of YAP/TAZ has been demonstrated in both the alveolar epithelium and activated fibroblasts associated with increased fibrotic remodeling, and there is emerging interest in this pathway as a target for antifibrotic therapies. In this review, we summarize current evidence as to the role of the Hippo-YAP/TAZ pathway in alveolar development, homeostasis, and repair, and highlight key questions that must be resolved to determine effective strategies to modulate YAP/TAZ signaling to prevent progressive pulmonary fibrosis and enhance adaptive alveolar repair.

Introduction: Adipose-derived stem cells (ADSCs) have been subject of several studies due to their abundance, ease of preparation, and application in bone regeneration. We aim to compare effectiveness of alveolar reconstruction utilizing human cancellous freeze-dried graft (HCG) and beta tricalcium phosphate (BTP), both seeded with human ADSC (hADSC) and autologous bone graft (ABG)., Material and Methods: A 5 × 5 mm alveolar defect in 36 male Wistar rats were treated using: ABG (C), HCG-hADSC (H1), and BTP-hADSC (H2). At 1 and 8 weeks after surgery, runt-related transcription factor 2 (RUNX2), alkaline phosphatase (ALP), osterix (OSX), and bone morphogenetic protein 2 (BMP2; g/mL) were quantified using immunohistochemistry, while bone tissue volume (BV, mm 3 ), bone tissue volume fraction (BF, percentage), and trabecular thickness of bone (TT, mm) were assessed using micro-computed tomography (CT)., Results: One week after surgery, H2 was higher in RUNX2, OSX, ALP, and BMP2 than C ( P  < .05). Only RUNX2 and OSX were found to be higher in H1 than C, while ALP and BMP2 were higher in H2 than H1. Micro-CT revealed that H2 had a higher TT than C and C had a higher TT than H1 ( P  < .05). Eight weeks after surgery, both H2 and H1 was higher in RUNX2, OSX, ALP, and BMP2 than C ( P  < .05). RUNX2 and BMP2 were found to be higher in H1 than H2. Micro-CT revealed that H2 had higher BV and TT than C and H1 ( P  < .05)., Conclusions: Exogenous hADSC strengthened the effectiveness of HCG and BTP to accelerate osteogenesis, osteoconduction, and osteoinduction. The latter was the most successful in bone formation, followed by HCG and ABG., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Chronic obstructive pulmonary disease (COPD) represents a worldwide concern with high morbidity and mortality, and is believed to be associated with accelerated ageing of the lung. Alveolar abnormalities leading to emphysema are a key characteristic of COPD. Pulmonary alveolar epithelial type 2 cells (AT2) produce surfactant and function as progenitors for type 1 cells. Increasing evidence shows elevated WNT-5A/B expression in ageing and in COPD that may contribute to the disease process. However, supportive roles for WNT-5A/B in lung regeneration were also reported in different studies. Thus, we explored the role of WNT-5A/B on alveolar epithelial progenitors (AEPs) in more detail. We established a Precision-Cut-Lung Slices (PCLS) model and a lung organoid model by co-culturing epithelial cells (EpCAM+/CD45-/CD31-) with fibroblasts in matrigel in vitro to study the impact of WNT-5A and WNT-5B. Our results show that WNT-5A and WNT-5B repress the growth of epithelial progenitors with WNT-5B preferentially restraining the growth and differentiation of alveolar epithelial progenitors. We provide evidence that both WNT-5A and WNT-5B negatively regulate the canonical WNT signaling pathway in alveolar epithelium. Taken together, these findings reveal the functional impact of WNT-5A/5B signaling on alveolar epithelial progenitors in the lung, which may contribute to defective alveolar repair in COPD.

Context: The prediction of implant treatment is directly influenced by the quality of the remaining bone after tooth extraction. Aims : The purpose of this experimental study was to, histologically and histometrically, evaluate the bone repair process in the central areas of extraction sockets filled with platelet-rich plasma. Materials and Methods: Four young adult male Cebus apella monkeys were used. The extraction of both right and left inferior second premolars was accomplished. After extraction, in one of the extraction sockets, coagulum was maintained while in the other it was removed; the alveolus was dried with gauze compress and filled up with platelet concentrate. For PRP production, Sonnleitner′s protocol was followed. The specimens for histological and histometric assessment were obtained in 30, 90, 120 and 180 days intervals. Results: In 30 days new bone formation was intense in both experimental and control sockets and no significant differences were observed between the two groups. After 90 days of the extraction, while the control group showed signs of decrease in osteogenesis, in the experimental unit, the process of bone formation and fibroblast-like cell proliferation remained intense. After 120 days, the PRP treated socket was occupied by large trabeculae of bone. After 180 days, the control unit was occupied mostly with bone marrow. The experimental unit remained occupied with large amounts of bone tissue. Conclusions: It was possible to conclude that bone repair was enhanced by the use of platelet- rich plasma in alveolar sockets.

The aim of the study was to determine the effects of retinoic acid on lung alveolar repair in adult hyperoxic mice and to investigate the relationship between TGF-β1 and retinoic acid during the repair processes. Adult mice were divided into 4 groups. Two groups were given daily intraperitoneal injections of peanut oil/dimethylsulfoxide mixture and retinoic acid (50mg/kg body weight, 50μl of volume) dissolved in peanut oil/dimethylsulfoxide mixture for 12 days with a 2-day break on days 6 and 7. Following hyperoxia (100% oxygen) for 72h the remaining two groups were treated in the same manner as already described: peanut oil/dimethylsulfoxide mixture and retinoic acid. Lung structure was investigated by light microscopy. TGF-β1 and Smad protein expressions in the lung were assayed by biochemical methods. Hyperoxic mice exhibited damage to the alveolar walls, increased cell proliferation and induced Smad3/TGF-β1 signaling. Smad2 and phospho-Smad2 protein expressions were unchanged in all groups. Retinoic acid administration improved the degenerative alterations caused by hyperoxia and helped in alveolar repair. This positive effect of retinoic acid resulted from the inhibition of Smad3/TGF-β1 signaling via reduced Smad4 mRNA and increased Smad7 protein expression. Retinoic acid also induced alveolarization and restricted Smad3/TGF-β1 signaling by decreasing Smad4 mRNA in healthy mice. Thus, retinoic acid helped repair Smad3/TGF-β1-induced lung damage in hyperoxic mice. [ABSTRACT FROM AUTHOR]

ABSTRACT The aim of the present research was to analyze ultrastructural and immunohistochemical aspects of the alveolar repair after the extraction of molars of alendronate (ALN)-treated rats. Wistar rats received 2.5mg/kg body wt/day of ALN during 14 days previously and 7, 14 and 21 days after the extraction of the second mandibular molar. Specimens were fixed in 2% glutaraldehyde + 2.5% formaldehyde under microwave irradiation, decalcified in 4.13% EDTA and paraffin embedded for TRAP histochemistry and immunohistochemistry for OPN, BSP and endoglin, or embedded in Spurr epoxy resin for TEM analysis. Additional specimens had their soft tissues removed and were processed for scanning electron microscopy. The ALN group presented latent TRAP-positive osteoclasts and nonresorbed alveolar crests with bacterial infection. Mild bone necrosis signs were observed at all time points studied. Ultrastructurally, empty osteocyte lacunae were observed and bone trabeculae surface presented hyalinized aspect. A significant delay in alveolar repair occurred, as well as decreased angiogenesis. ALN treatment provoked mild signs of bone necrosis, despite the high dose employed. The present findings add new information about the ultrastructural aspect of the early repair of rats under ALN treatment and highlight for giving attention when oral surgeries are performed in patients using this drug. Microsc. Res. Tech. 76:633-640, 2013. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Pulmonary emphysema is a major manifestation of chronic obstructive pulmonary disease (COPD), which is characterized by progressive destruction of alveolar parenchyma with persistent inflammation of the small airways. Such destruction in the distal respiratory tract is irreversible and irreparable. All-trans-retinoic acid was suggested as a novel therapy for regeneration of lost alveoli in emphysema. However, profound discrepancies were evident between studies. At present, no effective therapeutic options are available that allow for the regeneration of lost alveoli in emphysematous human lungs. Recently, some reports on rodent's models have suggested the beneficial effects of various growth factors toward alveolar maintenance and repair processes. [ABSTRACT FROM AUTHOR]

Pulmonary emphysema results from an excessive degradation of lung parenchyma associated with a failure of alveolar repair. Secretion by pulmonary fibroblasts of hepatocyte growth factor (HGF) and keratinocyte growth factor (KGF) is crucial to an effective epithelial repair after lung injury. We hypothesized that abnormal HGF or KGF secretion by pulmonary fibroblasts could play a role in the development of emphysema. We measured in vitro production of HGF and KGF by human fibroblasts cultured from emphysematous and normal lung samples. HGF and KGF production was quantified at basal state and after stimulation. Intracellular content of HGF was lower in emphysema (1.52 pg/µg, range of 0.15-7.40 pg/µg) than in control fibroblasts (14.16 pg/µg, range of 2.50-47.62 pg/µg; P = 0.047). HGF production by emphysema fibroblasts (19.3 pg/µg protein, range of 10.4-39.2 pg/µg) was lower than that of controls at baseline (57.5 pg/µg, range of 20.4-116 pg/µg; P = 0.019) and after stimulation with interleukin-1β or prostaglandin E2. Neither retinoic acids (alltrans and 9-cis) nor N-acetylcysteine could reverse this abnormality. KGF production by emphysema fibroblasts (5.3 pg/µg, range of 2.2-9.3 pg/µg) was similar to that of controls at baseline (2.6 pg/µg, range of 1-6.1 pg/µg; P = 0.14) but could not be stimulated with interleukin-1β. A decreased secretion of HGF by pulmonary fibroblasts could contribute to the insufficient alveolar repair in pulmonary emphysema. [ABSTRACT FROM AUTHOR]

Type II cells attach, migrate, and proliferate on a provisional fibronectin-rich matrix during alveolar wall repair after lung injury. The combination of cell-substratum interactions via integrin receptors and exposure to local growth factors are likely to initiate the signals required for cell proliferation, differentiation, reepithelialization, and ultimate restoration of the alveolar wall structure. Accordingly, primary cultured type II cells have been shown to bind fibronectin, in part through the α5β1 integrin, and to respond to growth factors that induce type II cell proliferation, such as fibroblast growth factor 1 (FGF-1). The purpose of this study was to determine whether or not FGF-1 modifies type II cell attachment to fibronectin, and if together they affect DNA synthesis. Attachment assays showed that FGF-1 treatment enhanced type II cell adhesion to fibronectin. This effect correlated with an increase in β1 integrin cell surface expression, and with the formation of cytoskeletal stabilizing structures such as lamellipodial extensions and stress fibers. FGF-1 also induced an increase in thymidine in corporation into DNA. Together FGF-1 and fibronectin appear to promote adhesion, cytoskeletal organization, and in creased DNA synthesis, and in this way influence cell-substratum interactions and signaling during alveolar repair. [ABSTRACT FROM AUTHOR]

Chronic obstructive pulmonary disease (COPD) represents a worldwide concern with high morbidity and mortality, and is believed to be associated with accelerated ageing of the lung. Alveolar abnormalities leading to emphysema are a key characteristic of COPD. Pulmonary alveolar epithelial type 2 cells (AT2) produce surfactant and function as progenitors for type 1 cells. Increasing evidence shows elevated WNT-5A/B expression in ageing and in COPD that may contribute to the disease process. However, supportive roles for WNT-5A/B in lung regeneration were also reported in different studies. Thus, we explored the role of WNT-5A/B on alveolar epithelial progenitors (AEPs) in more detail. We established a Precision-Cut-Lung Slices (PCLS) model and a lung organoid model by co-culturing epithelial cells (EpCAM+/CD45-/CD31-) with fibroblasts in matrigel in vitro to study the impact of WNT-5A and WNT-5B. Our results show that WNT-5A and WNT-5B repress the growth of epithelial progenitors with WNT-5B preferentially restraining the growth and differentiation of alveolar epithelial progenitors. We provide evidence that both WNT-5A and WNT-5B negatively regulate the canonical WNT signaling pathway in alveolar epithelium. Taken together, these findings reveal the functional impact of WNT-5A/5B signaling on alveolar epithelial progenitors in the lung, which may contribute to defective alveolar repair in COPD. [ABSTRACT FROM AUTHOR]