CXCR3-independent role of CXCL10 in alveolar epithelial repair.

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.

Paracrinal regulation of neutrophil functions by coronaviral infection in iPSC-derived alveolar type II epithelial cells.

Coronaviruses (CoVs) are enveloped single-stranded RNA viruses that predominantly attack the human respiratory system. In recent decades, several deadly human CoVs, including SARS-CoV, SARS-CoV-2, and MERS-CoV, have brought great impact on public health and economics. However, their high infectivity and the demand for high biosafety level facilities restrict the pathogenesis research of CoV infection. Exacerbated inflammatory cell infiltration is associated with poor prognosis in CoV-associated diseases. In this study, we used human CoV 229E (HCoV-229E), a CoV associated with relatively fewer biohazards, to investigate the pathogenesis of CoV infection and the regulation of neutrophil functions by CoV-infected lung cells. Induced pluripotent stem cell (iPSC)-derived alveolar epithelial type II cells (iAECIIs) exhibiting specific biomarkers and phenotypes were employed as an experimental model for CoV infection. After infection, the detection of dsRNA, S, and N proteins validated the infection of iAECIIs with HCoV-229E. The culture medium conditioned by the infected iAECIIs promoted the migration of neutrophils as well as their adhesion to the infected iAECIIs. Cytokine array revealed the elevated secretion of cytokines associated with chemotaxis and adhesion into the conditioned media from the infected iAECIIs. The importance of IL-8 secretion and ICAM-1 expression for neutrophil migration and adhesion, respectively, was demonstrated by using neutralizing antibodies. Moreover, next-generation sequencing analysis of the transcriptome revealed the upregulation of genes associated with cytokine signaling. To summarize, we established an in vitro model of CoV infection that can be applied for the study of the immune system perturbations during severe coronaviral disease.

ERK1/2-CEBPB Axis-Regulated hBD1 Enhances Anti-Tuberculosis Capacity in Alveolar Type II Epithelial Cells.

Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), remains a global health crisis with substantial morbidity and mortality rates. Type II alveolar epithelial cells (AEC-II) play a critical role in the pulmonary immune response against Mtb infection by secreting effector molecules such as antimicrobial peptides (AMPs). Here, human ß-defensin 1 (hBD1), an important AMP produced by AEC-II, has been demonstrated to exert potent anti-tuberculosis activity. HBD1 overexpression effectively inhibited Mtb proliferation in AEC-II, while mice lacking hBD1 exhibited susceptibility to Mtb and increased lung tissue inflammation. Mechanistically, in A549 cells infected with Mtb, STAT1 negatively regulated hBD1 transcription, while CEBPB was the primary transcription factor upregulating hBD1 expression. Furthermore, we revealed that the ERK1/2 signaling pathway activated by Mtb infection led to CEBPB phosphorylation and nuclear translocation, which subsequently promoted hBD1 expression. Our findings suggest that the ERK1/2-CEBPB-hBD1 regulatory axis can be a potential therapeutic target for anti-tuberculosis therapy aimed at enhancing the immune response of AEC-II cells.

Downregulated BMP-Smad1/5/8 signaling causes emphysema via dysfunction of alveolar type II epithelial cells.

Bone morphogenetic protein (BMP)-Smad1/5/8 signaling plays a crucial regulatory role in lung development and adult lung homeostasis. However, it remains elusive whether BMP-Smad1/5/8 signaling is involved in the pathogenesis of emphysema. In this study, we downregulated BMP-Smad1/5/8 signaling by overexpressing its antagonist Noggin in adult mouse alveolar type II epithelial cells (AT2s), resulting in an emphysematous phenotype mimicking the typical pathological features of human emphysema, including distal airspace enlargement, pulmonary inflammation, extracellular matrix remodeling, and impaired lung function. Dysregulation of BMP-Smad1/5/8 signaling in AT2s leads to inflammatory destruction dominated by macrophage infiltration, associated with reduced secretion of surfactant proteins and inhibition of AT2 proliferation and differentiation. Reactivation of BMP-Smad1/5/8 signaling by genetics or chemotherapy significantly attenuated the morphology and pathophysiology of emphysema and improved the lung function in Noggin-overexpressing lungs. We also found that BMP-Smad1/5/8 signaling was downregulated in cigarette smoke-induced emphysema, and that enhancing its activity in AT2s prevented or even reversed emphysema in the mouse model. Our data suggest that BMP-Smad1/5/8 signaling, located at the top of the signaling cascade that regulates lung homeostasis, represents a key molecular regulator of alveolar stem cell secretory and regenerative function, and could serve as a potential target for future prevention and treatment of pulmonary emphysema. © 2023 The Pathological Society of Great Britain and Ireland.

[Leptin-mediated ERK Signaling Pathway Promotes the Transformation 
of Rat Alveolar Type II Epithelial Cells Induced by Yunnan Tin Mine Dust].

BACKGROUND: Currently, a significant number of miners are involved in mining operations at the Gejiu tin mine in Yunnan. This occupational setting is associated with exposure to dust particles, heavy metals, polycyclic aromatic hydrocarbons, and radioactive radon, thereby significantly elevating the risk of lung cancer. This study aims to investigate the involvement of leptin-mediated extracellular regulated protein kinase (ERK) signaling pathway in the malignant transformation of rat alveolar type II epithelial cells induced by Yunnan tin mine dust. METHODS: Immortalized rat alveolar cells type II (RLE-6TN) cells were infected with Yunnan tin mine dust at a concentration of 200 µg/mL for nine consecutive generations to establish the infected cell model, which was named R200 cells. The cells were cultured normally, named as R cells. The expression of leptin receptor in both cell groups was detected using the Western blot method. The optimal concentration of leptin and mitogen-activated protein kinase kinase (MEK) inhibitor (U0126) on R200 cells was determined using the MTT method. Starting from the 20th generation, the cells in the R group were co-cultured with leptin, while the cells in the R200 group were co-cultured with the MEK inhibitor U0126. The morphological alterations of the cells in each group were visualized utilizing hematoxylin-eosin staining. Additionally, concanavalin A (ConA) was utilized to detect any morphological differences, and an anchorage-independent growth assay was conducted to assess the malignant transformation of the cells. The changes in the ERK signaling pathway in epithelial cells after the action of leptin were detected using the Western blot method. RESULTS: Both the cells in the R group and R200 group express leptin receptor OB-R. Compared to the R200 group, the concentration of leptin at 100 ng/mL shows the most significant pro-proliferation effect. The proliferation of R200 cells infected with the virus is inhibited by 30 µmol/L U0126, and a statistically significant divergence was seen when compared to the control group (P<0.05). Starting from the 25th generation, the cell morphology of the leptin-induced R200 group (R200L group) underwent changes, leading to malignant transformation observed at the 30th generation. The characteristics of malignant transformation became evident by the 40th generation in the R200L group. In contrast, the other groups showed agglutination of P40 cells, and the speed of cell aggregation increased with an increase in ConA concentration. Notably, the R200L group exhibited faster cell aggregation compared to the U0126-induced R200 (R200LU) group. Additionally, the cells in the R200L group were capable of forming clones starting from P30, with a colony formation rate of 2.25‰±0.5‰. However, no clonal colonies were observed in the R200LU group and R200 group. The expression of phosphorylated extracellular signal-regulated kinase (pERK) was enhanced in cells of the R200L group. However, when the cells in the R200L group were treated with U0126, a blocking agent, the phosphorylation level of pERK decreased. CONCLUSIONS: Leptin can promote the malignant transformation of lung epithelial cells infected by mine dust, and the ERK signaling pathway may be necessary for the transformation of alveolar type II epithelial cells induced by Yunnan tin mine dust.

ILC2 influence the differentiation of alveolar type II epithelial cells in bronchopulmonary dysplasia mice.

Bronchopulmonary dysplasia, a common complication of premature infants, is mainly characterized by blocked alveolarization. Proverbially, the injury of alveolar type II epithelial cells is regarded as the pathologic basis of occurrence and development of bronchopulmonary dysplasia. In the case of alveolar epithelial damage, alveolar type II epithelial cells can also differentiate to alveolar type I epithelial cells as progenitor cells. During bronchopulmonary dysplasia, the differentiation of alveolar type II epithelial cells becomes abnormal. Group 2 innate lymphoid cells can produce type 2 cytokines in response to a variety of stimuli, including the epithelial cytokines IL-25, IL-33, and thymic stromal lymphopoietin. Previous studies have shown that group 2 innate lymphoid cells can inhibit the alveolarization process of bronchopulmonary dysplasia by secreting IL-13. However, whether group 2 innate lymphoid cells can affect the differentiation of alveolar type II epithelial cells in the pathologic process of bronchopulmonary dysplasia remains unclear. In this study, we have shown that IL-13 secreted by group 2 innate lymphoid cells increased during bronchopulmonary dysplasia, which was related to the release of large amounts of IL-33 by impaired alveolar type II epithelial cells. This led to abnormal differentiation of alveolar type II epithelial cells, reduced differentiation to alveolar type I epithelial cells, and increased transdifferentiation to mesenchymal cells through the epithelial-mesenchymal transition. Taken together, our study provides a complementary understanding of the development of bronchopulmonary dysplasia and highlights a novel immune mechanism in the pathogenesis of bronchopulmonary dysplasia.

Impaired autophagy-accelerated senescence of alveolar type II epithelial cells drives pulmonary fibrosis induced by single-walled carbon nanotubes.

BACKGROUND: The rapid increase in production and application of carbon nanotubes (CNTs) has led to wide public concerns in their potential risks to human health. Single-walled CNTs (SWCNTs), as an extensively applied type of CNTs, have shown strong capacity to induce pulmonary fibrosis in animal models, however, the intrinsic mechanisms remain uncertain. RESULTS: In vivo experiments, we showed that accelerated senescence of alveolar type II epithelial cells (AECIIs) was associated with pulmonary fibrosis in SWCNTs-exposed mice, as well as SWCNTs-induced fibrotic lungs exhibited impaired autophagic flux in AECIIs in a time dependent manner. In vitro, SWCNTs exposure resulted in profound dysfunctions of MLE-12 cells, characterized by impaired autophagic flux and accelerated cellular senescence. Furthermore, the conditioned medium from SWCNTs-exposed MLE-12 cells promoted fibroblast-myofibroblast transdifferentiation (FMT). Additionally, restoration of autophagy flux with rapamycin significantly alleviated SWCNTs-triggered senescence and subsequent FMT whereas inhibiting autophagy using 3-MA aggravated SWCNTs-triggered senescence in MLE-12 cells and FMT. CONCLUSION: SWCNTs trigger senescence of AECIIs by impairing autophagic flux mediated pulmonary fibrosis. The findings raise the possibility of senescence-related cytokines as potential biomarkers for the hazard of CNTs exposure and regulating autophagy as an appealing target to halt CNTs-induced development of pulmonary fibrosis.

Efficacy of Alveolar Type II Epithelial Cell Transplantation for Pulmonary Fibrosis: A Meta-Analysis.

Background: Cell transplantation is a promising therapeutic strategy for pulmonary fibrosis. In order to clarify the alveolar type II epithelial cell potential utility in the treatment of lung disease, we conducted a meta-analysis, to evaluate alveolar type II epithelial cells in animal models of lung injury and pulmonary fibrosis. Methods: This review followed the recommendations from the PRISMA statements, Comprehensive retrieval method was used to search Embase, PubMed, Cochrane, Chinese Knowledge Infrastructure, VIP and Wanfang databases. A total of 7 studies and 286 model rats were included. Two researchers independently screened the identified studies, based on inclusion and exclusion criteria. All analyses were conducted using Review Manager V.5.3 software. The combined standard mean difference (SMD) and 95% confidence interval (CI) of data from the included studies were calculated using fixed or random-effects models. Results: The analysis of three outcome indexes showed that the heterogeneity of the oxygen saturation group was high (I2=85%), the lung weight group (I2=64%) was close to moderate heterogeneity, and the lung hydroxyproline content group (I2=0) was not heterogeneous. Conclusion: Meta-analysis showed that transplantation of alveolar type II epithelial cells has beneficial effects, and no obvious adverse reactions. Alveolar type II epithelial cell transplantation can significantly reduce the intervention group and lung hydroxyproline content weight, improve the blood oxygen saturation, lung histo-pathology showed significant improvement in pulmonary fibrosis.

Leptin-mediated ERK Signaling Pathway Promotes the Transformation of Rat Alveolar Type II Epithelial Cells Induced by Yunnan Tin Mine Dust / 中国肺癌杂志

BACKGROUND@#Currently, a significant number of miners are involved in mining operations at the Gejiu tin mine in Yunnan. This occupational setting is associated with exposure to dust particles, heavy metals, polycyclic aromatic hydrocarbons, and radioactive radon, thereby significantly elevating the risk of lung cancer. This study aims to investigate the involvement of leptin-mediated extracellular regulated protein kinase (ERK) signaling pathway in the malignant transformation of rat alveolar type II epithelial cells induced by Yunnan tin mine dust.@*METHODS@#Immortalized rat alveolar cells type II (RLE-6TN) cells were infected with Yunnan tin mine dust at a concentration of 200 μg/mL for nine consecutive generations to establish the infected cell model, which was named R₂₀₀ cells. The cells were cultured normally, named as R cells. The expression of leptin receptor in both cell groups was detected using the Western blot method. The optimal concentration of leptin and mitogen-activated protein kinase kinase (MEK) inhibitor (U0126) on R₂₀₀ cells was determined using the MTT method. Starting from the 20th generation, the cells in the R group were co-cultured with leptin, while the cells in the R₂₀₀ group were co-cultured with the MEK inhibitor U0126. The morphological alterations of the cells in each group were visualized utilizing hematoxylin-eosin staining. Additionally, concanavalin A (ConA) was utilized to detect any morphological differences, and an anchorage-independent growth assay was conducted to assess the malignant transformation of the cells. The changes in the ERK signaling pathway in epithelial cells after the action of leptin were detected using the Western blot method.@*RESULTS@#Both the cells in the R group and R₂₀₀ group express leptin receptor OB-R. Compared to the R₂₀₀ group, the concentration of leptin at 100 ng/mL shows the most significant pro-proliferation effect. The proliferation of R₂₀₀ cells infected with the virus is inhibited by 30 μmol/L U0126, and a statistically significant divergence was seen when compared to the control group (P<0.05). Starting from the 25th generation, the cell morphology of the leptin-induced R₂₀₀ group (R₂₀₀L group) underwent changes, leading to malignant transformation observed at the 30th generation. The characteristics of malignant transformation became evident by the 40th generation in the R₂₀₀L group. In contrast, the other groups showed agglutination of P40 cells, and the speed of cell aggregation increased with an increase in ConA concentration. Notably, the R₂₀₀L group exhibited faster cell aggregation compared to the U0126-induced R₂₀₀ (R₂₀₀LU) group. Additionally, the cells in the R₂₀₀L group were capable of forming clones starting from P30, with a colony formation rate of 2.25‰±0.5‰. However, no clonal colonies were observed in the R₂₀₀LU group and R₂₀₀ group. The expression of phosphorylated extracellular signal-regulated kinase (pERK) was enhanced in cells of the R₂₀₀L group. However, when the cells in the R₂₀₀L group were treated with U0126, a blocking agent, the phosphorylation level of pERK decreased.@*CONCLUSIONS@#Leptin can promote the malignant transformation of lung epithelial cells infected by mine dust, and the ERK signaling pathway may be necessary for the transformation of alveolar type II epithelial cells induced by Yunnan tin mine dust.

The Promising Therapeutic Approaches for Radiation-Induced Pulmonary Fibrosis: Targeting Radiation-Induced Mesenchymal Transition of Alveolar Type II Epithelial Cells.

Radiation-induced pulmonary fibrosis (RIPF) is a common consequence of radiation for thoracic tumors, and is accompanied by gradual and irreversible organ failure. This severely reduces the survival rate of cancer patients, due to the serious side effects and lack of clinically effective drugs and methods. Radiation-induced pulmonary fibrosis is a dynamic process involving many complicated and varied mechanisms, of which alveolar type II epithelial (AT2) cells are one of the primary target cells, and the epithelial-mesenchymal transition (EMT) of AT2 cells is very relevant in the clinical search for effective targets. Therefore, this review summarizes several important signaling pathways that can induce EMT in AT2 cells, and searches for molecular targets with potential effects on RIPF among them, in order to provide effective therapeutic tools for the clinical prevention and treatment of RIPF.

Senescent AECâ ¡ and the implication for idiopathic pulmonary fibrosis treatment.

Idiopathic pulmonary fibrosis (IPF) is a chronic and lethal lung disease with limited treatment options. The onset of IPF increases with age, indicating that aging is a major risk factor for IPF. Among the hallmarks of aging, cellular senescence is the primordial driver and primary etiological factor for tissue and organ aging, and an independent risk factor for the progression of IPF. In this review, we focus on the senescence of alveolar type II epithelial cells (AECIIs) and systematically summarize abnormal changes in signal pathways and biological process and implications of senescent AECIIs during IPF progression. Meanwhile, we objectively analyze current medications targeting the elimination of senescent cells or restoration of vitality such as senolytics, senomorphics, autophagy regulators, and stem cell therapy. Finally, we dialectically discuss the feasibility and limitation of targeting senescent AECIIs for IPF treatment. We hope that the understanding will provide new insights to the development of senescent AECII-based approaches for the prevention and mitigation of IPF.

Dysfunctional lactate metabolism in human alveolar type II cells from idiopathic pulmonary fibrosis lung explant tissue.

BACKGROUND: Idiopathic Pulmonary Fibrosis (IPF) is the most common and progressive form of the interstitial lung diseases, leading most patients to require lung transplants to survive. Despite the relatively well-defined role of the fibroblast in the progression of IPF, it is the alveolar type II epithelial cell (AEC2) that is now considered the initiation site of damage, driver of disease, and the most efficacious therapeutic target for long-term resolution. Based on our previous studies, we hypothesize that altered lactate metabolism in AEC2 plays a pivotal role in IPF development and progression, affecting key cellular and molecular interactions within the pulmonary microenvironment. METHODS: AEC2s isolated from human patient specimens of non-fibrotic and IPF lungs were used for metabolic measurements, lactate dehydrogenase (LDH) analyses and siRNA-mediated knockdown experiments. RESULTS: AEC2s isolated from human IPF lung explant tissues had lower rates of oxidative metabolism and were more glycolytic lactate-producing cells than were AEC2 from control, non-fibrotic lung explant tissues. Consistent with this shift in metabolism, patient-derived IPF AEC2s exhibited LDH tetramers that have higher ratios of LDHA:LDHB (i.e., favoring pyruvate to lactate conversion) than control AEC2s. Experimental manipulation of LDHA subunit expression in IPF AEC2s restored the bioenergetic profile characteristic of AEC2 from non-fibrotic lungs. CONCLUSIONS: These results are consistent with the concept that altered lactate metabolism may be an underlying feature of AEC2 dysfunction in IPF and may be a novel and important target for therapeutic treatment.

LRRK2 plays essential roles in maintaining lung homeostasis and preventing the development of pulmonary fibrosis.

Perturbation of lung homeostasis is frequently associated with progressive and fatal respiratory diseases, such as pulmonary fibrosis. Leucine-rich repeat kinase 2 (LRRK2) is highly expressed in healthy lungs, but its functions in lung homeostasis and diseases remain elusive. Herein, we showed that LRRK2 expression was clearly reduced in mammalian fibrotic lungs, and LRRK2-deficient mice exhibited aggravated bleomycin-induced pulmonary fibrosis. Furthermore, we demonstrated that in bleomycin-treated mice, LRRK2 expression was dramatically decreased in alveolar type II epithelial (AT2) cells, and its deficiency resulted in profound dysfunction of AT2 cells, characterized by impaired autophagy and accelerated cellular senescence. Additionally, LRRK2-deficient AT2 cells showed a higher capacity of recruiting profibrotic macrophages via the CCL2/CCR2 signaling, leading to extensive macrophage-associated profibrotic responses and progressive pulmonary fibrosis. Taken together, our study demonstrates that LRRK2 plays a crucial role in preventing AT2 cell dysfunction and orchestrating the innate immune responses to protect against pulmonary fibrosis.

Nanomedicine for acute respiratory distress syndrome: The latest application, targeting strategy, and rational design.

Acute respiratory distress syndrome (ARDS) is characterized by the severe inflammation and destruction of the lung air-blood barrier, leading to irreversible and substantial respiratory function damage. Patients with coronavirus disease 2019 (COVID-19) have been encountered with a high risk of ARDS, underscoring the urgency for exploiting effective therapy. However, proper medications for ARDS are still lacking due to poor pharmacokinetics, non-specific side effects, inability to surmount pulmonary barrier, and inadequate management of heterogeneity. The increased lung permeability in the pathological environment of ARDS may contribute to nanoparticle-mediated passive targeting delivery. Nanomedicine has demonstrated unique advantages in solving the dilemma of ARDS drug therapy, which can address the shortcomings and limitations of traditional anti-inflammatory or antioxidant drug treatment. Through passive, active, or physicochemical targeting, nanocarriers can interact with lung epithelium/endothelium and inflammatory cells to reverse abnormal changes and restore homeostasis of the pulmonary environment, thereby showing good therapeutic activity and reduced toxicity. This article reviews the latest applications of nanomedicine in pre-clinical ARDS therapy, highlights the strategies for targeted treatment of lung inflammation, presents the innovative drug delivery systems, and provides inspiration for strengthening the therapeutic effect of nanomedicine-based treatment.

Baicalin attenuates LPS-induced alveolar type II epithelial cell A549 injury by attenuation of the FSTL1 signaling pathway via increasing miR-200b-3p expression.

In China, baicalin is the main active component of Scutellaria baicalensis, which has been used in the treatment of inflammation-related diseases, such as inflammation-induced acute lung injury. However, its specific mechanism remains unclear. This study examined the protective effect of baicalin on LPS-induced inflammation injury of alveolar epithelial cell line A549 and explored its protective mechanism. Compared with the LPS-induced group, the proliferation inhibition rates of alveolar type II epithelial cell line A549 intervened by different concentrations of baicalin decreased significantly, as did the levels of inflammatory factors IL-6, IL-1ß, prostaglandin 2 and TNF-α in the supernatant. The expression levels of inflammatory proteins inducible NO synthase (iNOS), NF-κB65, phosphorylated ERK (p-ERK1/2), and phosphorylated c-Jun N-terminal kinase (p-JNK1) significantly decreased, as did the protein expression of follistatin-like protein 1 (FSTL1). In contrast, expression of miR-200b-3p significantly increased in a dose-dependent manner. These results suggested that baicalin could significantly inhibit the expression of inflammation-related proteins and improve LPS-induced inflammatory injury in alveolar type II epithelial cells. The mechanism may be related to the inhibition of ERK/JNK inflammatory pathway activation by increasing the expression of miR-200b-3p. Thus, FSTL1 is the regulatory target of miR-200b-3p.

Nanomedicine for acute respiratory distress syndrome: The latest application, targeting strategy, and rational design

Acute respiratory distress syndrome (ARDS) is characterized by the severe inflammation and destruction of the lung air-blood barrier, leading to irreversible and substantial respiratory function damage. Patients with coronavirus disease 2019 (COVID-19) have been encountered with a high risk of ARDS, underscoring the urgency for exploiting effective therapy. However, proper medications for ARDS are still lacking due to poor pharmacokinetics, non-specific side effects, inability to surmount pulmonary barrier, and inadequate management of heterogeneity. The increased lung permeability in the pathological environment of ARDS may contribute to nanoparticle-mediated passive targeting delivery. Nanomedicine has demonstrated unique advantages in solving the dilemma of ARDS drug therapy, which can address the shortcomings and limitations of traditional anti-inflammatory or antioxidant drug treatment. Through passive, active, or physicochemical targeting, nanocarriers can interact with lung epithelium/endothelium and inflammatory cells to reverse abnormal changes and restore homeostasis of the pulmonary environment, thereby showing good therapeutic activity and reduced toxicity. This article reviews the latest applications of nanomedicine in pre-clinical ARDS therapy, highlights the strategies for targeted treatment of lung inflammation, presents the innovative drug delivery systems, and provides inspiration for strengthening the therapeutic effect of nanomedicine-based treatment.

Maimendong Decoction Improves Pulmonary Function in Rats With Idiopathic Pulmonary Fibrosis by Inhibiting Endoplasmic Reticulum Stress in AECIIs.

This study was designed to investigate the mechanism by which MMDD improves lung function, and observe the effect of MMDD on endoplasmic reticulum stress(ERS) in alveolar type II epithelial cells (AECIIs) of pulmonary fibrosis rats. pulmonary fibrosis animal model was established by intratracheal injection of BLM at a dose of 6mg/kg body weight. Overall, Thirty male SPF Sprague-Dawley rats were randomly divided into control group, BLM group and BLM+MMDD group. BLM+MMDD group rats were fed 24 g/kg over three weeks for twice a day on the fourteenth day after model establishment. MMDD improves pulmonary function of fibrotic rats and reduces the occurrence of endoplasmic reticulum stress in AECIIs. MMDD could significantly improve the forced vital capacity (FVC) of bleomycin-induced pulmonary fibrosis in rats. MMDD reduced the expression of GRP78 and CHOP in AECIIs, increased the secretion of surfactant protein C (SPC) by AECIIs. Moreover, the apoptosis of the fibrosis zone in the lung tissue was remarkably mitigated by administration of MMDD. The finding of this study revealed that MMDD can improve lung function in rats with pulmonary fibrosis by reducing the occurrence of ERS and cell apoptosis of AECIIs. It may provide a new method for the treatment of pulmonary fibrosis.

Klebsiella pneumoniae infection inhibits autophagy by alveolar type II epithelial cells.

To investigate the molecular mechanism underlying the interaction between autophagosomes of alveolar type II epithelial (A549) cells and Klebsiella pneumoniae, an in vitro model of K. pneumoniae-infected A549 cells was established. Western blot analysis and immunofluorescence staining were used to detect the distribution of microtubule-associated protein 1A/1B-light chain 3 (LC3) and the expression of the LC3-phosphatidylethanolamine conjugate (LC3-II). K. pneumoniae-infected A549 cells were treated with different concentrations of an autophagy inhibitor or promoter for different time periods to assess the level of autophagy. Western blot analysis and immunofluorescence staining showed that K. pneumoniae could induce autophagy by A549 cells. With an increase in bacterial concentration and time of infection, autophagy gradually increased. The autophagy inhibitor significantly downregulated, while the promoter upregulated, expression of the autophagy-related protein LC3-II. Autophagy plays an important role in the resistance of alveolar type II epithelial (A549) cells to K. pneumoniae infection.

Effects of Different Ligands in the Notch Signaling Pathway on the Proliferation and Transdifferentiation of Primary Type II Alveolar Epithelial Cells.

Background: Transdifferentiation of type II alveolar epithelial cells (AECII) into type I alveolar epithelial cells (AECI) is involved in neonatal respiratory distress syndrome (NRDS). Different ligands of the Notch pathway could have different effects on AECII transdifferentiation. Objective: To investigate the effects of Dlk1 and Jagged1 on the proliferation and transdifferentiation of AECII. Methods: Fetal AECIIs (19 days of gestation) were divided: control group, Dlk1 group, rhNF-κB group. Proliferation was tested using the MTT assay. Expression of surfactant protein C (SP-C) and aquaporin 5 (AQP5) was examined by immunofluorescence. mRNA and protein levels of SP-C, AQP5, Nortch1, Dlk1, Jagged1, and Hes1 were examined by RT-PCR and western blot. Results: In response to Dlk1, cell number and proliferation were increased (P < 0.05), and mRNA and protein levels of SP-C, Dlk1, Notch1, and Hes1 were up-regulated, while AQP and Jagged1 were decreased. In response to rhNF-κB, the cell number and proliferation were reduced, and mRNA and protein levels of Jagged1 and Notch1 were up-regulated, while Dlk1, and SP-C were downregulated. In the Dlk1 group, SP-C, and AQP5 expression patterns suggested that the cells were still transdifferentiating by 96 h, while in the rhNF-κB group, most cells had transdifferentiated by 72 h and were close to apoptosis by 96 h. Conclusion: These results suggest that Dlk1 promoted proliferation of AECIIs and inhibited cell transdifferentiation, while Jagged1 treatment inhibited proliferation of AECIIs and promoted transdifferentiation to AECIs. These results provide some clue for the eventual management of NDRS.