ST218 Klebsiella pneumoniae became a high-risk clone for multidrug resistance and hypervirulence.

BACKGROUND: The occurrence of multidrug-resistant and hypervirulent Klebsiella pneumoniae (MDR-hvKp) worldwide poses a great challenge for public health. Few studies have focused on ST218 MDR-hvKp. METHODS: Retrospective genomic surveillance was conducted at the Peking University Third Hospital from 2017 and clinical information was obtained. To understand genomic and microbiological characteristics, antimicrobial susceptibility testing, plasmid conjugation and stability, biofilm formation, serum killing, growth curves and whole-genome sequencing were performed. We also assessed the clinical and microbiological characteristics of ST218 compared with ST23. RESULTS: A total of eleven ST218 Kp isolates were included. The most common infection type was lower respiratory tract infection (72.7%, 8/11) in our hospital, whereas ST23 hvKp (72.7%, 8/11) was closely associated with bloodstream infection. Notably, nosocomial infections caused by ST218 (54.5%, 6/11) was slightly higher than ST23 (36.4%, 4/11). All of the ST218 and ST23 strains presented with the virulence genes combination of iucA + iroB + peg344 + rmpA + rmpA2. Interestingly, the virulence score of ST218 was lower than ST23, whereas one ST218 strain (pPEKP3107) exhibited resistance to carbapenems, cephalosporins, ß-lactamase/inhibitors and quinolones and harbored an ~ 59-kb IncN type MDR plasmid carrying resistance genes including blaNDM-1, dfrA14 and qnrS1. Importantly, blaNDM-1 and qnrS1 were flanked with IS26 located within the plasmid that could successfully transfer into E. coli J53. Additionally, PEKP2044 harbored an ~ 41-kb resistance plasmid located within tetA indicating resistance to doxycycline. CONCLUSION: The emergence of blaNDM-1 revealed that there is great potential for ST218 Kp to become a high-risk clone for MDR-hvKp, indicating the urgent need for enhanced genomic surveillance.

Association between angiotensin-converting enzyme inhibitor-induced cough and the risk of lung cancer: a Mendelian randomization study.

Background: Observational studies and meta-analyses have demonstrated a positive correlation between the use of angiotensin-converting enzyme inhibitors (ACEIs) and lung cancer. However, the findings remain controversial; furthermore, the relationship between ACEI-induced cough and lung cancer development remains unknown. We used Mendelian randomization (MR) to verify the association between ACEI use, ACEI-induced cough, and the risk of lung cancer. Methods: We performed a two-sample MR analysis to determine the unconfounded relationships between ACE inhibition, which mimics the effects of ACEIs, and genetic proxies for ACEI-induced cough and lung cancer. Single nucleotide polymorphisms that imitate ACE receptors and ACEI-induced cough were collected and integrated into a meta-analysis of existing genome-wide association studies for various lung cancers. The relationship was quantified using inverse variance weighting, weighted median, and MR-Egger methods. Results: A statistically significant association was observed between ACE inhibition and the risk of small cell lung cancer for Europeans (excluding rs118121655/rs80311894). Associations were identified between ACEI-induced cough and the risk of lung cancer for Europeans, although not for Asians, and between ACEI-induced cough and lung adenocarcinoma (excluding rs360206). Conclusion: Our findings reveal a relationship between ACE inhibition and lung cancer development, as well as a significant association between ACEI-induced cough and a higher risk of lung cancer for Europeans. Patients with hypertension who experience dry cough as a side effect of ACEI use should consider switching to an alternative antihypertensive treatment.

Siderophore-mediated iron partition promotes dynamical coexistence between cooperators and cheaters.

Microbes shape their habitats by consuming resources and producing a diverse array of chemicals that can serve as public goods. Despite the risk of exploitation by cheaters, genes encoding sharable molecules like siderophores are widely found in nature, prompting investigations into the mechanisms that allow producers to resist invasion by cheaters. In this work, we presented the chemostat-typed "resource partition model" to demonstrate that dividing the iron resource between private and public siderophores can promote stable or dynamic coexistence between producers and cheaters in a well-mixed environment. Moreover, our analysis shows that when microbes not only consume but also produce resources, chemical innovation leads to stability criteria that differ from those of classical consumer resource models, resulting in more complex dynamics. Our work sheds light on the role of chemical innovations in microbial communities and the potential for resource partition to facilitate dynamical coexistence between cooperative and cheating organisms.

Understanding how various forms of phosphorus stress affect microbiome functions and boost plant disease resistance: Insights from metagenomic analysis.

The plant's response to phosphorus (P) starvation suppresses its immunity and regulates rhizosphere microbial colonization. However, the impact of various P forms on plant disease resistance and microbial composition remains underreported. This paper examines the soybean rhizosphere microbiome facing co-stress from Fusarium oxysporum and diverse P forms. Macrogenomic analysis evaluates whether P addition enhances plant disease resistance and rhizosphere microbial function, and if such effects relate to P forms. Results show that different P forms mitigate F. oxysporum-induced plant inhibition by promoting P turnover. P forms predominantly affect microbial composition, followed by soil and plant properties. In soybean, the phosphate transport strategy (ugpA/Q) was selected to maintain high P to enhance immunity in the KH2PO4 treatment, while organo-P mineralization (phnH/F/W/G) was selected for superphosphate treatment. The Frankiales, a P-turnover microorganism, copiotrophic microorganisms, and indicator bacteria of plant properties, initially increase after F. oxysporum inoculation and then decrease post P addition, regardless of P forms. Additionally, the rhizosphere microbial community's metabolic activities and compounds significantly aid soybean defense against F. oxysporum, with functional types depending on P forms. Therefore, these findings establish a novel approach to enhance host defense against soil-borne diseases through P nutrition regulation to mediate host-driven metabolic activities of microbial communities.

Assessing the promoting effect of compound microbial agents on flax dew retting: Based on the relationship between metabolites and core genera.

In this study, 16S rRNA sequencing and GC-MS (gas chromatography-mass spectrometry) techniques were employed to examine the relationship between bacterial succession and metabolite alterations during the dew retting process of flax. The results indicated that the addition of compound microbial agents may affect the production and transformation of metabolites by re-establishing bacterial communities and promoting the degradation of pectic substances and the release of metabolites, and the best retting effect was achieved under the combined addition (BA). In addition, Chryseobacterium, Bacillus, and Pseudoonas were closely associated with the production of fatty acids and alcohols; the addition of compound microbial agents increased the content of critical metabolites while decreasing the environmental pollutant bis(2-ethylhexyl) phthalate. In summary, the addition of compound microbial agents can positively regulate the retting process of flax, shorten the retting cycle, improve the quality of flax fibre, and reduce the pollution of the environment.

Characterization of Bacillus spp. isolated from the intestines of Rhynchocypris lagowskii as a potential probiotic and their effects on fish pathogens.

Probiotics sourced from fish intestinal microbiota have a merit over other bacterial sources due to colonization ability and effective time. This study aimed to evaluate the bacilli isolated from the Rhynchocypris lagowskii intestines and their validity as a probiotic. Three isolates were selected (LSG 2-5, LSG 3-7, and LSG 3-8) and defined by morphological and 16S rRNA analysis as Bacillus velezensis, Bacillus aryabhattai, and Bacillus mojavensis, respectively. Results showed the strain tolerant abilities to gastrointestinal fluid, bile salt, pH, and temperature expotures. Additionally, all bacterial strains showed anti-pathogenic activity against at least four strains out of six tested pathogen strains (Staphylococcus aureus, Aeromonas hydrophila, Escherichia coli, Aeromonas veronii, Edwardsiella, and Aeromonas sobria). The bacterial strains also showed a high percentage of co-aggregation activity, more than 70%, with Aer. hydrophile, Staph. epidermidis, and Klebsiella aerogenes. At the same time, the results of competition, rejection, and substitution activity with Aer. hydrophila and Aer. veronii indicated the ability of the isolated strains to reduce the adhesion of pathogens to mucin. All strains showed safety properties, non-hemolytic, and sensitivity characteristics for most of tested antibiotics. In vivo test after injecting these strains into fish at various concentrations showed no side effects in the internal or external organs of fish compared to controls, proving that this is safe for these fish. Furthermore, the three strains produced lipase, amylase, and protease enzymes. The strains also showed bile salt hydrolase activity and biofilm formation, allowing them to tolerate stressful conditions. Conclusion: Based on these strains characteristics and features, they could be considered a promising candidate probiotic and can be used as an anti-pathogenic, especially in aquaculture.

Response characteristics of flax retting liquid addition during chicken manure composting: Focusing on core bacteria in organic carbon mineralization and humification.

To explore the applicability of flax retting liquid (FRL) addition, the physicochemical properties, microbial community structure and function, carbon conversion and humus (HS) formation were assessed during chicken manure (CM) aerobic composting. Compared with the control group, the addition of FRL increased the temperature at thermophilic phase, while the microbial mass carbon content (MBC) in SCF and FRH groups raised to 96.1 ± 0.25 g/Kg and 93.33 ± 0.27 g/Kg, respectively. Similarly, FRL also improved the concent of humic acid (HA) to 38.44 ± 0.85 g/Kg, 33.06 ± 0.8 g/Kg, respcetively. However, fulvic acid (FA) decreased to 30.02 ± 0.55 g/Kg, 31.4 ± 0.43 g/Kg, respectively and further reduced CO2 emissions. FRL influenced the relative abundance of Firmicutes at thermophilic phase and Ornithinimicrobium at maturity phase. Additionally, FRL strengthen the association among flora and reduce the number of bacteria, which was negative correlated with HA and positive with CO2 during composting. These findings offer powerful technological support for improving agricultural waste recycling.

Association between angiotensin-converting enzyme inhibitors and the risk of lung cancer: a systematic review and meta-analysis.

BACKGROUND: The association between the use of angiotensin-converting enzyme inhibitors (ACEIs) and lung cancer risk remains controversial. This study evaluated the association between the use of ACEIs and lung cancer risk. METHODS: Records from five databases were searched from inception to 26 January 2022. Clinical studies involving persons aged ≥18 years with at least one year of follow-up and reporting adverse events, including lung cancer, were recorded with separate outcome reports supplied for the ACEIs and control groups. Data were extracted independently by three authors and pooled using a random-effects model. The primary outcome was lung cancer development. Odds ratios (ORs) with 95% confidence intervals (CIs) and lung cancer-related morbidity were calculated. RESULTS: Of 2400 records screened, 13,061,226 patients were included from seven cohort studies and four case-control studies. Pooled results showed that ACEIs use was linked to increased lung cancer risk (OR 1.19, 95% CI 1.05-1.36; P = 0.008), with high heterogeneity (I2 = 98%). CONCLUSIONS: ACEI usage is a greater risk factor for lung carcinogenesis than angiotensin receptor blocker use, especially in Asian patients. Further randomised controlled trials are needed to confirm the causal association between the use of ACEIs and lung cancer risk.

Exogenous glutathione reverses meropenem resistance in carbapenem-resistant Klebsiella pneumoniae.

Background: The rate of carbapenem-resistant Klebsiella pneumoniae (CRKP) infection has been increasing rapidly worldwide and, poses a significant risk to human health. Effective methods are urgently needed to address treatment failures related to antibiotic resistance. Recent research has reported that some drugs in combination with antibiotics have displayed synergistic killing of resistant bacteria. Here, we investigated whether glutathione (GSH) can synergize with meropenem, and enhance its effectiveness against CRKP. Methods: Synergistic activity was assessed by checkerboard and time-killing assays. The mechanism of these combinations was assessed by total ROS and membrane permeability assays. The bacterial metabolites were assessed by LC‒MS/MS. Results: The FICIs of GSH and meropenem were approximately 0.5 and the combined treatment with GSH and meropenem resulted in a more than 2log10 CFU/mL reduction in bacteria compared to the individual treatments. These findings indicated the synergistic effect of the two drugs. Moreover, the meropenem MIC of CRKP was reduced to less than 4 mg/L when combined with 6 mg/mL GSH, indicating that GSH could significantly reverse resistance to meropenem in bacteria. The production of ROS in bacteria was determined by flow cytometry. After adding GSH, the ROS in the GSH group and the combined group was significantly higher than that in the control and meropenem groups, but there was no significant difference between the combined and GSH groups. The metabolic disturbance caused by GSH alone and in combination with meropenem was significant intracellularly and extracellularly, especially in terms of glycerophospholipid metabolism, indicating that the synergistic effect of the combined use of GSH and meropenem was relevant to glycerophospholipid metabolism. In addition, we measured the cell membrane permeability. The cell membrane permeability of the combination group was significantly higher than that of the blank control or monotreatment groups. This confirmed that the GSH can serve as a meropenem enhancers by disturbing glycerophospholipid metabolism and increasing cell membrane permeability. Conclusion: GSH and meropenem display a synergistic effect, wherein GSH increases the sensitivity of CRKP to meropenem. The synergy and susceptibility effects are thought to related to the increased membrane permeability resulting from the perturbations in glycerophospholipid metabolism, presenting a novel avenue for CRKP treatment.

Clinical Outcomes, Microbiological Characteristics and Risk Factors for Difficult-to-Treat Resistance to Klebsiella pneumoniae Infection.

Purpose: This study aimed to identify the clinical outcomes, microbiological features and risk factors for difficult-to-treat resistance (DTR) Klebsiella pneumoniae (Kp) infection. Materials and Methods: A retrospective study was conducted at Peking University Third Hospital from January 2020 to March 2021. DTR was defined as resistance to ≥1 carbapenem, ≥1 extended-spectrum cephalosporin, and ≥1 fluoroquinolone. Hypervirulent Kp (HvKp) was defined as peg-344-, iroB-, iucA-, rmpA-, or rmpA2-positive. Clinical data were collected. Antimicrobial susceptibility testing and string tests were performed to determine resistance and hypermucoviscosity phenotype. Whole genome sequencing was performed to analyze the sequence type (ST), capsular serotypes, resistance and virulence genes. Risk factors for 30-day mortality were analyzed. Results: Fifty DTR-Kp (50.0%) strains were identified among 100 patients. Compared to non-DTR-Kp group, a significant number of patients with DTR-Kp infection experienced ICU admission (44.0% versus 10.0%, P<0.001) and mechanical ventilation after Kp detection (26.0% versus 10.0%, P=0.037). Notably, the percentage of hvKp among the DTR-Kp isolates increased consistently over the 15 months evaluated. Most DTR-Kp strains belonged to ST11 (82.0%), followed by ST15 (12.0%), ST86 (2.0%), ST996 (2.0%), and ST3157 (2.0%). DTR-Kp isolates possessed various resistance genes, such as blaKPC-2, blaTEM-1D and fosA3 (90.0%, 80.0% and 72.0%, respectively). Importantly, the yersiniabactin genes were significantly clustered in DTR group (48/50, 96.0%). The 30-day mortality was significantly higher in patients with DTR-Kp infection than non-DTR-Kp group (38.0% versus 8.2%, P=0.001). DTR-Kp infection (odds ratio [OR] = 4.196) was an independent risk factor for the 30-day mortality of Kp-infected patients. Additionally, cerebrovascular disease (OR = 2.780) and Charlson comorbidity index (OR= 1.584) were independent risk factors for DTR-Kp infections. Conclusion: DTR-hvKp is rapidly emerging. The DTR-Kp strains harbored various resistance genes and high rates of yersiniabactin siderophore genes. DTR-Kp infection was an independent risk factor for mortality, suggesting that enhanced awareness essential.

Remdesivir in treating hospitalized patients with COVID-19: A renewed review of clinical trials.

Since December 2019, COVID-19 has spread across the world almost through 2.5 years. As of 16 June 2022, the cumulative number of confirmed cases of COVID-19 worldwide has reached 542.62 million, and the death toll has risen to 6.33 million. With the increasing number of deaths, it is urgent to find effective treatment drugs. Remdesivir, an investigational broad-spectrum antiviral drug produced by Gilead has been shown to inhibit SARS-CoV-2, in vitro and in vivo. This review is aimed to analyze the feasibility of remdesivir in COVID-19 and put forward the shortcomings of present clinical studies. We systematically searched PubMed and Web of Science up until 24 May 2022, using several specific terms such as "remdesivir" or "GS-5734" and "COVID-19" or "SARS-CoV-2" and retrieved basic researches and clinical studies of remdesivir in COVID-19. In this review, we summarized and reviewed the mechanism of remdesivir in SARS-COV-2, clinical trials of using remdesivir in COVID-19, analyzed the efficacy and safety of remdesivir, and judged whether the drug was effective for the treatment of COVID-19. In different clinical trials, remdesivir showed a mixed result in the treatment of COVID-19. It seemed that remdesivir shortened the time to recovery and had an acceptable safety profile. However, more clinical trials are needed to test the efficacy and safety of remdesivir.

A zero-sum game or an interactive frame? Iron competition between bacteria and humans in infection war.

ABSTRACT: Iron is an essential trace element for both humans and bacteria. It plays a vital role in life, such as in redox reactions and electron transport. Strict regulatory mechanisms are necessary to maintain iron homeostasis because both excess and insufficient iron are harmful to life. Competition for iron is a war between humans and bacteria. To grow, reproduce, colonize, and successfully cause infection, pathogens have evolved various mechanisms for iron uptake from humans, principally Fe 3+ -siderophore and Fe 2+ -heme transport systems. Humans have many innate immune mechanisms that regulate the distribution of iron and inhibit bacterial iron uptake to help resist bacterial invasion and colonization. Meanwhile, researchers have invented detection test strips and coupled antibiotics with siderophores to create tools that take advantage of this battle for iron, to help eliminate pathogens. In this review, we summarize bacterial and human iron metabolism, competition for iron between humans and bacteria, siderophore sensors, antibiotics coupled with siderophores, and related phenomena. We also discuss how competition for iron can be used for diagnosis and treatment of infection in the future.

Inhibitory effect of probiotic Bacillus spp. isolated from the digestive tract of Rhynchocypris Lagowskii on the adhesion of common pathogenic bacteria in the intestinal model.

Diseases of fish caused by pathogenic bacteria are an important constraint on aquaculture production. Antibiotics have been widely used to control infectious diseases, but this has led to the emergence of drug-resistant bacteria and affected human health. In this context, probiotics are used as an alternative to antibiotics for the prevention and control of diseases in aquaculture. The aim of this study was to obtain probiotic candidate strains of Bacillus spp. from the gut of Rhynchocypris Lagowskii. Strains were screened by enzyme-producing ability, antagonism assay and antibiotic susceptibility. The safety of the strains to host fish has also been established. The isolated Bacillus licheniformis (LSG1-1) and Bacillus subtilis (LSG2-1) were characterized and performed well in tolerance experiments. In addition, LSG1-1 and LSG2-1 were detected to have higher self-aggregation ability and surface hydrophobicity. In the in vitro adhesion model, LSG1-1 and LSG2-1 showed good adhesion ability and had obvious adhesion inhibitory effect on three pathogens of Aeromonas. Based on the characteristics observed so far, Bacillus licheniformis LSG1-1 and Bacillus subtilis LSG2-1 could form potential probiotic candidates in the digestive tract of R. lagowskii to help combat diseases in aquaculture.

Clinical Outcomes and Microbiological Characteristics of Sequence Type 11 Klebsiella pneumoniae Infection.

Background: Sequence type 11 (ST11) Klebsiella pneumoniae (Kp) is highly prevalent in China and is a typical sequence type among KPC-producing isolates. This study aimed to evaluate the clinical outcomes and microbiological features of ST11 Kp infections. Methods: A retrospective cohort study was conducted at Peking University Third Hospital from January 2017 to March 2021. Clinical data were collected from medical records. Antimicrobial susceptibility testing and string tests were performed. Whole-genome sequencing was used to analyze the capsular serotypes, detect virulence-associated genes, and perform multilocus sequence typing. The risk of all-cause mortality in ST11 Kp-infected patients was compared to that in non-ST11 Kp-infected patients. Results: From 139 patients infected with Kp, 49 ST11 Kp (35.3%) strains were isolated. The Charlson comorbidity index in the ST11 group was higher than that in the non-ST11 group (3.94 ± 1.59 vs. 2.41 ± 1.54, P = 0.001). A greater number of ST11 Kp-infected patients required ICU admission (46.9 vs. 16.7%, P < 0.001) and mechanical ventilation (28.6 vs. 10.0%, P = 0.005). All ST11 isolates presented a multidrug-resistant (MDR) phenotype, and twenty-nine (59.2%) hypervirulent Kp (hvKp) were identified. Twenty-four ST11 strains presented with hypermucoviscosity. The presence of capsular types K47 and K64 was frequent in the ST11 Kp strains (P < 0.001). The key virulence-associated genes rmpA, rmpA2, iucA, iroB, and peg344 were present in 26.5, 42.9, 59.2, 0, and 26.5% of the isolates, respectively, in the ST11 group. Twenty-one ST11 isolates harbored the combination of iucA+rmpA2. The 30-day mortality rate and sequential organ failure assessment (SOFA) score were significantly higher in ST11 Kp-infected patients than in non-ST11 Kp-infected patients (P < 0.01). ST11 Kp infection appeared to be an independent risk factor for mortality in ST11 Kp-infected patients. Conclusions: A high prevalence of the ST11 clone was found in the hospital, which accounted for elevated antimicrobial resistance and exhibited great molecularly inferred virulence. Patients with ST11 Kp infection had a tendency toward increased 30-day mortality and SOFA scores. ST11 Kp infection was an independent risk factor for mortality, suggesting that enhanced surveillance and management are essential.

Nasal nitric oxide testing for allergic rhinitis patients: Systematic review and meta-analysis.

BACKGROUND: Nasal nitric oxide (nNO) levels in allergic rhinitis (AR), healthy people or nonallergic rhinitis (NAR) have shown contradicting results in previous studies. By meta-analysis, we reviewed studies that measured nNO in AR patients to assess nNO's ability to discriminate AR from healthy people or NAR. METHODS: We systematically searched PubMed, Cochrane, Embase, Ovid, Web of Science, Wanfang Data, CNKI until December 15, 2020. Differences were expressed as standardized mean differences (SMD) with 95% confidence interval (CI), by random-effects method. RESULTS: A total of 10 original studies with 561 AR patients, 327 healthy controls, 123 NAR patients were included in the narrative synthesis and 9 studies in the meta-analysis. nNO in AR was significantly increased compared with healthy controls (SMD: 0.989; 95% CI: 0.402, 1.576; p = .001) or NAR (SMD: 0.680; 95% CI: 0.101, 1.259; p = 0.021). However, subgroup analysis based on measuring process and patient characteristics showed that no significant differences were detected in nNO between AR patients with nasal polyps or sinusitis or marked ostial obstruction and healthy controls. CONCLUSIONS: nNO is a potential indicator for recognizing AR. Nasal polyps, sinusitis and marked ostial obstruction should be considered before nNO is applied to detect AR.

Role of the Bronchodilator Test Defined by the Forced Vital Capacity in Chronic Obstructive Pulmonary Disease Phenotyping.

Purpose: In clinical practice, some chronic obstructive pulmonary disease (COPD) patients experienced a remarkable increase in forced vital capacity (FVC) after bronchodilator administration, whereas forced expiratory volume in the first second (FEV1) remains substantially unchanged. We assume this may relate to airway inflammatory type. We aim to analyze the clinical characteristics and explore the usefulness of the bronchodilator test, especially FVC, in this new COPD phenotype. Patients and Methods: A total of 346 COPD patients with exacerbation who underwent bronchodilator tests, fractional exhaled nitric oxide (FeNO) measurements and blood eosinophil counts were analyzed. The characteristics, FeNO levels, and blood eosinophil counts were compared between patients with and without significant bronchodilator responsiveness in terms of FVC. Results: Patients with significant FVC responsiveness displayed poorer lung function and higher FeNO levels compared with those without considerable FVC responsiveness (Z= -5.042 to -0.375, p=0.000-0.022). There is a discernible linear relationship between FeNO levels and FVC responsiveness to bronchodilator use (r=0.251, P=0.001). The application of bronchodilator responsiveness of FVC for detecting high FeNO levels in COPD patients exhibited relatively high sensitivity (61.8%) and specificity (86.7%). Conclusion: We demonstrated that COPD patients with significant FVC responsiveness had higher FeNO levels than non-responders and established a simple method for detecting high FeNO values. FVC responders may be identified as a separate group of COPD patients.

Small airway remodeling in diabetic and smoking chronic obstructive pulmonary disease patients.

Diabetes mellitus can reinforce the small airway dysfunction of chronic obstructive pulmonary disease (COPD) patients. The epithelial-mesenchymal transition (EMT) that is associated with small airway remodeling is activated in the airway epithelial cells (AECs) of both COPD patients and diabetic patients. Transforming growth factor ß (TGF-ß) can induce EMT via the TGF-ß/Smad pathway. We found that the small airway dysfunction and airflow limitations were worse in COPD patients with a history of smoking or diabetes than in simple COPD patients, and were even worse in COPD patients with both histories. Pulmonary ventilation tests in rats confirmed these findings. EMT and the TGF-ß/Smad pathway were activated in the AECs of rats with COPD or diabetes, and the combination of COPD and diabetes amplified those effects, as indicated by downregulation of Zo1 and upregulation of vimentin, TGF-ß and Smad4 in immunohistochemical experiments. Twenty-four-hour treatment with 25 mM glucose and/or 1% cigarette smoke extract upregulated vimentin, TGF-ß, Smad2/3/4 and p-Smad2/3, but downregulated Zo1 in AECs. Suppressing the TGF-ß/Smad pathway prevented EMT activation and small airway remodeling following cigarette smoke exposure and hyperglycemia. Thus, cigarette smoke and high glucose exposure induces EMT via the TGF-ß/Smad pathway in AECs.

ß2-microglobulin as a biomarker of pulmonary fibrosis development in COPD patients.

Expression of ß2-microglobulin (ß2M) is involved in fibrosis progression in kidney, liver, and heart. In this case-controlled retrospective study, we investigated the role of ß2M in the development of pulmonary fibrosis in patients with chronic obstructive pulmonary disease (COPD). Analysis of 450 COPD patients revealed that patients with decreased pulmonary diffusing capacity (DLCO) had increased ß2M serum levels. Compared to patients with lower ß2M serum levels, patients with increased ß2M levels exhibited increased alveolar wall/septal thickening and lung tissue ß2M expression. In addition, patients with increased ß2M levels had increased lung expression of TGF-ß1, Smad4, and a-SMA. Animal experiments showed that increased ß2M expression resulted in epithelial-mesenchymal transition (EMT), alveolar wall/septal thickening, and pulmonary fibrosis in a rat COPD model. Together, these results indicate that ß2M serum levels may serve as a new indicator for assessment of pulmonary diffusion function and pulmonary fibrosis severity in clinical practice and may provide a potential target for treatment of pulmonary fibrosis in the future.