Club Cell Secretory Protein-16 (CC16) as a Prognostic Biomarker for COVID-19 and H1N1 Viral Infections.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and H1N1 viruses are inflammatory lung pathogens that can lead to acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). ALI/ARDS are still life-threatening diseases in critically ill patients with 30-40% mortality in the last decade. Currently, there are no laboratory tests for the early diagnosis or prognosis of ALI/ARDS. Club cell secretory protein (CC16) has been investigated as a potential biomarker of lung epithelial damage in various lung diseases. In this study, we evaluated whether plasma CC16 reflects the severity of COVID-19 and H1N1 infections. The plasma CC16 levels showed no significant differences between H1N1 and COVID-19 groups (p = 0.09). Among all subjects, CC16 levels were significantly higher in non-survivors than in survivors (p = 0.001). Upon the area under the receiver operating characteristic (AUROC) analysis, CC16 had an acceptable value to distinguish survivors and non-survivors (p = 0.002). In the COVID-19 group, plasma CC16 levels moderately correlated with the Acute Physiology and Chronic Health Evaluation II (APACHE II) score (r = 0.374, p = 0.003) and Sequential Organ Failure Assessment (SOFA) score (r = 0.474, p < 0.001). In the H1N1 group, a positive correlation was observed between the CC16 levels and hospital length of stay (r = 0.311, p = 0.022). Among all the patients, weak correlations between plasma CC16 levels with the SOFA score (r = 0.328, p < 0.001) and hospital length of stay (r = 0.310, p < 0.001) were observed. Thus, circulating CC16 might reflect the severity of COVID-19 and H1N1 infections.

Clara cell 10 (CC10) protein attenuates allergic airway inflammation by modulating lung dendritic cell functions.

Allergic asthma is a complex inflammatory disorder predominantly orchestrated by T helper 2 (Th2) lymphocytes. The anti-inflammatory protein Clara Cell 10-kDa (CC10), also known as secretoglobin family 1A member 1 (SCGB1A1), shows promise in modulating respiratory diseases. However, its precise role in asthma remains unclear. This study examines the potential of CC10 to suppress allergic asthma inflammation, specifically assessing its regulatory effects on Th2 cell responses and dendritic cells (DCs). Lower CC10 levels in asthma were observed and correlated with increased IgE and lymphocytes. Cc10-/- mice exhibited exacerbated allergic airway inflammation marked by increased inflammatory cell infiltration, Th2 cytokines, serum antigen-specific IgE levels, and airway hyperresponsiveness (AHR) in house dust mite (HDM)-induced models. Conversely, recombinant CC10 significantly attenuated these inflammatory responses. Intriguingly, CC10 did not directly inhibit Th cell activation but significantly downregulated the population of CD11b+CD103- DCs subsets in lungs of asthmatic mice and modulated the immune activation functions of DCs through NF-κB signaling pathway. The mixed lymphocyte response assay revealed that DCs mediated the suppressive effect of CC10 on Th2 cell responses. Collectively, CC10 profoundly mitigates Th2-type allergic inflammation in asthma by modulating lung DC phenotype and functions, highlighting its therapeutic potential for inflammatory airway conditions and other related immunological disorders.

Diagnostic Performance of Plasma SP-D, KL-6, and CC16 in Acutely Hospitalised Patients Suspected of Having Community-Acquired Pneumonia-A Diagnostic Accuracy Study.

Community-acquired pneumonia is a common cause of acute hospitalisation. Identifying patients with community-acquired pneumonia among patients suspected of having the disease can be a challenge, which causes unnecessary antibiotic treatment. We investigated whether the circulatory pulmonary injury markers surfactant protein D (SP-D), Krebs von den Lungen-6 (KL-6), and Club cell protein 16 (CC16) could help identify patients with community-acquired pneumonia upon acute admission. In this multi-centre diagnostic accuracy study, SP-D, KL-6, and CC16 were quantified in plasma samples from acutely hospitalised patients with provisional diagnoses of community-acquired pneumonia. The area under the receiver operator characteristics curve (AUC) was calculated for each marker against the following outcomes: patients' final diagnoses regarding community-acquired pneumonia assigned by an expert panel, and pneumonic findings on chest CTs. Plasma samples from 339 patients were analysed. The prevalence of community-acquired pneumonia was 63%. AUCs for each marker against both final diagnoses and chest CT diagnoses ranged between 0.50 and 0.56. Thus, SP-D, KL-6, and CC16 demonstrated poor diagnostic performance for community-acquired pneumonia in acutely hospitalised patients. Our findings indicate that the markers cannot readily assist physicians in confirming or ruling out community-acquired pneumonia.

Estrogen regulated transcription of the non-estrogen-regulated hamster uteroglobin gene in MCF-7 cells.

To study the estrogen regulated transcription of the uteroglobin (UG) gene, the founding member of the secretoglobin family widely expressed in many different mammalian species, we re-created functional estrogen response elements (EREs) in the UG gene promoter from a species where UG expression is not regulated by estrogens: the hamster Mesocricetus auratus (Ma), to ascertain if the lack of functional EREs is the real cause of its estrogen insensitivity. Functional EREs in the hamster promoter, including the consensus ERE (cERE), failed to respond to an appropriate estrogen stimulus compared with its estrogen regulated ortholog from the brown hare Lepus capensis (Lc). As the nucleotide sequence is the only difference between genetic constructs from these two species, we suspected that the UG promoter from the hamster probably contains cis-acting genetic elements that negatively impairs the estrogen-regulated transcription mediated by the functional ERE. Accordingly, we prepared chimeric DNA constructs which eventually allowed to identify a region located 29 base pairs (bp) downstream of the ERE as responsible for the lack of estrogen-responsiveness of the Ma-UG gene in the breast cancer cell line MCF-7. This region contains the sequence ACACCCC which has been identified as the core sequence of the Sp/ Krüppel-like factor (KLF) family of transcription factors. This finding is relevant, not only due to the observation on a novel mechanism that control estrogen-induced transcription, but also because it may encourage further investigation for better defining specific genes with an ERE that do not respond to estrogen signaling in MCF-7 cells, a cell line widely employed as an in vitro model in breast cancer research.

Club Cell Secretory Protein in Lung Disease: Emerging Concepts and Potential Therapeutics.

Club cell secretory protein (CCSP), also known as secretoglobin 1A1 (gene name SCGB1A1), is one of the most abundant proteins in the lung, primarily produced by club cells of the distal airway epithelium. At baseline, CCSP is found in large concentrations in lung fluid specimens and can also be detected in the blood and urine. Obstructive lung diseases are generally associated with reduced CCSP levels, thought to be due to decreased CCSP production or club cell depletion. Conversely, several restrictive lung diseases have been found to have increased CCSP levels both in the lung and in the circulation, likely related to club cell dysregulation as well as increasedlung permeability. Recent studies demonstrate multiple mechanisms by which CCSP dampens acute and chronic lung inflammation. Given these anti-inflammatory effects, CCSP represents a novel potential therapeutic modality in lung disease.

Club cell protein (CC)16 as potential lung injury marker in a porcine 72 h polytrauma model.

BACKGROUND: Polytrauma and respiratory tract damage after thoracic trauma cause about 25% of mortality among severely injured patients. Thoracic trauma can lead to the development of severe lung complications such as acute respiratory distress syndrome, and is, therefore, of great interest for monitoring in intensive care units (ICU). In recent years, club cell protein (CC)16 with its antioxidant properties has proven to be a potential outcome-related marker. In this study, we evaluated whether CC16 constitutes as a marker of lung damage in a porcine polytrauma model. METHODS: In a 72 h ICU polytrauma pig model (thoracic trauma, tibial fracture, hemorrhagic shock, liver laceration), blood plasma samples (0, 3, 9, 24, 48, 72 h), BAL samples (72 h) and lung tissue (72 h) were collected. The trauma group (PT) was compared to a sham group. CC16 as a possible biomarker for lung injury in this model, and IL-8 concentrations as known indicator for ongoing inflammation during trauma were determined by ELISA. Histological analysis of ZO-1 and determination of total protein content were used to show barrier disruption and edema formation in lung tissue from the trauma group. RESULTS: Systemic CC16 levels were significantly increased early after polytrauma compared vs. sham. After 72 h, CC16 concentration was significantly increased in lung tissue as well as in BAL in PT vs. sham. Similarly, IL-8 and total protein content in BAL were significantly increased in PT vs. sham. Evaluation of ZO-1 staining showed significantly lower signal intensity for polytrauma. CONCLUSION: The data confirm for the first time in a larger animal polytrauma model that lung damage was indicated by systemic and/or local CC16 response. Thus, early plasma and late BAL CC16 levels might be suitable to be used as markers of lung injury in this polytrauma model.

Associação entre proteína 1 relacionada à uteroglobulina e gravidade da lesão por inalação de fumaça / Association of uteroglobin-related protein 1 with smoke inhalation injury severity

RESUMO Objetivo: Avaliar a expressão sérica da proteína 1 relacionada à uteroglobulina na fase inicial após lesões por inalação de fumaça e sua associação com a gravidade da lesão por inalação em pacientes queimados. Métodos: A lesão por inalação de fumaça ou produtos químicos se associa com morbidade e mortalidade. As consequências da inalação resultam de uma resposta inflamatória. A proteína 1 relacionada à uteroglobulina é anti-inflamatória e pode melhorar a inflamação pulmonar. Nossa hipótese é que os níveis de proteína 1 relacionada à uteroglobulina podem refletir a gravidade da doença e predizer o desfecho em pacientes com lesão por inalação. Incluíram-se prospectivamente neste estudo 16 pacientes com diagnóstico de síndrome do desconforto respiratório agudo decorrente de lesão por inalação de fumaça. Em todos os pacientes, colheu-se amostra de plasma quando da admissão à unidade de terapia intensiva, para avaliar a gravidade da lesão por inalação dentro de 72 horas. Os níveis plasmáticos de proteína 1 relacionada à uteroglobulina foram determinados em duplicata por meio de ensaio de imunoabsorção ligado à enzima. Resultados: A média de idade foi de 23 ± 5 anos, e a distribuição da lesão por inalação foi: três em grau 1, quatro em grau 2 e nove em grau 3. O nível de proteína 1 relacionada à uteroglobulina foi relacionado ao grau de severidade (grau 1: 0,389 ± 0,053 unidade arbitrária versus grau 2: 0,474 ± 0,0423 unidade arbitrária versus grau 3: 0,580 ± 0,094 unidade arbitrária; p = 0,007). Conclusão: Os níveis plasmáticos de proteína 1 relacionada à uteroglobulina se associam com o grau da lesão pulmonar por inalação.

ABSTRACT Objective: To evaluate serum uteroglobin-related protein 1 expression early after smoke inhalation injuries and its association with the severity of inhalation injury in burned patients. Methods: Smoke or chemical inhalation injury is associated with morbidity and mortality. The consequences of inhalation result from an inflammatory response. Uteroglobin-related protein 1 is an anti-inflammatory protein and may improve lung inflammation. We hypothesized that uteroglobin-related protein 1 levels could reflect disease severity and predict outcome in patients with inhalation injury. Sixteen patients diagnosed with acute respiratory distress syndrome secondary to smoke inhalation injury were prospectively included in the study. Plasma was collected upon intensive care unit admission and within 24 hours of the inhalation injury. Bronchoscopies were carried out in all patients to assess the severity of inhalation injury within 72 hours. Uteroglobin-related protein 1 plasma levels were determined in duplicate with enzyme-linked immunosorbent assay. Results: The mean age was 23 ± 5 years, and the inhalation injury distribution was as follows: three of grade 1, four of grade 2, and nine of grade 3. The level of uteroglobin-related protein 1 was related to inhalation severity (grade 1: 0.389 ± 0.053 arbitrary units versus grade 2: 0.474 ± 0.0423 arbitrary units versus grade 3: 0.580 ± 0.094 arbitrary units; p = 0.007). Conclusion: Plasma levels of uteroglobin-related protein 1 are associated with the degree of lung inhalation injury.

Endogenous Uteroglobin as Intrinsic Anti-inflammatory Signal Modulates Monocyte and Macrophage Subsets Distribution Upon Sepsis Induced Lung Injury.

Sepsis is a serious clinical condition which can cause life-threatening organ dysfunction, and has limited therapeutic options. The paradigm of limiting excessive inflammation and promoting anti-inflammatory responses is a simplified concept. Yet, the absence of intrinsic anti-inflammatory signaling at the early stage of an infection can lead to an exaggerated activation of immune cells, including monocytes and macrophages. There is emerging evidence that endogenous molecules control those mechanisms. Here we aimed to identify and describe the dynamic changes in monocyte and macrophage subsets and lung damage in CL57BL/6N mice undergoing blunt chest trauma with subsequent cecal ligation and puncture. We showed that early an increase in systemic and activated Ly6C+CD11b+CD45+Ly6G- monocytes was paralleled by their increased emigration into lungs. The ratio of pro-inflammatory Ly6ChighCD11b+CD45+Ly6G- to patrolling Ly6ClowCD11b+CD45+Ly6G- monocytes significantly increased in blood, lungs and bronchoalveolar lavage fluid (BALF) suggesting an early transition to inflammatory phenotypes during early sepsis development. Similar to monocytes, the level of pro-inflammatory Ly6ChighCD45+F4/80+ macrophages increased in lungs and BALF, while tissue repairing Ly6ClowCD45+F4/80+ macrophages declined in BALF. Levels of inflammatory mediators TNF-α and MCP-1 in blood and RAGE in lungs and BALF were elevated, and besides their boosting of inflammation via the recruitment of cells, they may promote monocyte and macrophage polarization, respectively, toward the pro-inflammatory phenotype. Neutralization of uteroglobin increased pro-inflammatory cytokine levels, activation of inflammatory phenotypes and their recruitment to lungs; concurrent with increased pulmonary damage in septic mice. In in vitro experiments, the influence of uteroglobin on monocyte functions including migratory behavior, TGF-ß1 expression, cytotoxicity and viability were proven. These results highlight an important role of endogenous uteroglobin as intrinsic anti-inflammatory signal upon sepsis-induced early lung injury, which modules the early monocyte/macrophages driven inflammation. Short Summary: Blunt chest injury is the third largest cause of death following major trauma, and ongoing excessive pro-inflammatory immune response entails high risk for the development of secondary complications, such as sepsis, with limited therapeutic options. In murine double hit trauma consisting of thoracic trauma and subsequent cecal ligation and puncture, we investigated the cytokine profile, pulmonary epithelial integrity and phenotypic shift of patrolling Ly6ClowCD11b+CD45+Ly6G- monocytes and Ly6ClowCD45+F4/80+ macrophages to pro-inflammatory Ly6ChighCD11b+CD45+Ly6G- monocytes and Ly6ChighCD45+F4/80+ cells in blood, lungs and bronchoalveolar lavage fluid (BALF). Pro-inflammatory mediators and phenotypes were elevated and uteroglobin neutralization led to further increase. Enhanced total protein levels in BALF suggests leakage of respiratory epithelium. In vitro, uteroglobin inhibited the migratory capacity of monocytes and the TGF-ß1 expression without affecting the viability. These results highlight an important role of endogenous uteroglobin as an intrinsic anti-inflammatory signal upon sepsis-induced early lung injury, which modulates the early monocyte/macrophages driven inflammation.

Early Local Inhibition of Club Cell Protein 16 Following Chest Trauma Reduces Late Sepsis-Induced Acute Lung Injury.

Blunt thoracic trauma (TxT) deteriorates clinical post-injury outcomes. Ongoing inflammatory changes promote the development of post-traumatic complications, frequently causing Acute Lung Injury (ALI). Club Cell Protein (CC)16, a pulmonary anti-inflammatory protein, correlates with lung damage following TxT. Whether CC16-neutralization influences the inflammatory course during ALI is elusive. Ninety-six male CL57BL/6N mice underwent a double hit model of TxT and cecal ligation puncture (CLP, 24 h post-TxT). Shams underwent surgical procedures. CC16 was neutralized by the intratracheal application of an anti-CC16-antibody, either after TxT (early) or following CLP (late). Euthanasia was performed at 6 or 24 h post-CLP. Systemic and pulmonary levels of IL-6, IL-1ß, and CXCL5 were determined, the neutrophils were quantified in the bronchoalveolar lavage fluid, and histomorphological lung damage was assessed. ALI induced a significant systemic IL-6 increase among all groups, while the local inflammatory response was most prominent after 24 h in the double-hit groups as compared to the shams. Significantly increased neutrophilic infiltration upon double hit was paralleled with the enhanced lung damage in all groups as compared to the sham, after 6 and 24 h. Neutralization of CC16 did not change the systemic inflammation. However, early CC16-neutralization increased the neutrophilic infiltration and lung injury at 6 h post-CLP, while 24 h later, the lung injury was reduced. Late CC16-neutralization increased neutrophilic infiltration, 24 h post-CLP, and was concurrent with an enhanced lung injury. The data confirmed the anti-inflammatory potential of endogenous CC16 in the murine double-hit model of ALI.

Club Cell Secretory Protein Deficiency Leads to Altered Lung Function.

RATIONALE: CC16 (club cell secretory protein-16), a member of the secretoglobin family, is one of the most abundant proteins in normal airway secretions and has been described as a serum biomarker for obstructive lung diseases. OBJECTIVES: To determine whether low CC16 is a marker for airway pathology or is implicated in the pathophysiology of progressive airway damage in these conditions. METHODS: Using human data from the birth cohort of the Tucson Children's Respiratory Study, we examined the relation of circulating CC16 levels with pulmonary function and responses to bronchial methacholine challenge from childhood up to age 32 years. In wild-type and CC16-/- mice, we set out to comprehensively examine pulmonary physiology, inflammation, and remodeling in the naive airway. MEASUREMENTS AND MAIN RESULTS: We observed that Tucson Children's Respiratory Study participants in the lowest tertile of serum CC16 had significant deficits in their lung function and enhanced airway hyperresponsiveness to methacholine challenge from 11 years throughout young adult life. Similarly, CC16-/- mice had significant deficits in lung function and enhanced airway hyperresponsiveness to methacholine as compared with wild-type mice, which were independent of inflammation and mucin production. As compared with wild-type mice, CC16-/- mice had significantly elevated gene expression of procollagen type I, procollagen type III, and α-smooth muscle actin, areas of pronounced collagen deposition and significantly enhanced smooth muscle thickness. CONCLUSIONS: Our findings support clinical observations by providing evidence that lack of CC16 in the lung results in dramatically altered pulmonary function and structural alterations consistent with enhanced remodeling.

Uteroglobin and FLRG concentrations in aqueous humor are associated with age in primary open angle glaucoma patients.

BACKGROUND: The pathophysiological changes occurring in the trabecular meshwork in primary open angle glaucoma are poorly understood, but are thought to include increased extracellular matrix deposition, trabecular meshwork cell apoptosis, inflammation, trabecular meshwork calcification and altered protein composition of the aqueous humor. Although many proteins are present in aqueous humor, relatively few have been studied extensively, and their potential roles in primary open angle glaucoma are unknown. METHODS: Analyte concentrations in aqueous humor from 19 primary open angle glaucoma and 18 cataract patients were measured using a multiplex immunoassay. Fisher's exact test was used to assess statistical significance between groups, and correlations of analyte concentrations with age, intraocular pressure, pattern standard deviation, mean deviation, cup-to-disc ratio and disease duration since commencing treatment were tested by Spearman's method. RESULTS: CHI3L1, FLRG, HGF, MIF, P-selectin and Uteroglobin were detected in more than 50% of samples of one or both patient groups, some of which have not previously been quantified in aqueous humor. In the glaucoma but not the cataract group, significant correlations were determined with age for Uteroglobin/SCGB1A1 (rs = 0.805, p < 0.0001) and FLRG (rs = 0.706, p = 0.0007). Furthermore, HGF correlated significantly with disease duration (rs = - 0.723, p = 0.0007). There were no differences in analyte concentrations between groups, and no other significant associations with clinical descriptors that passed correction for multiple testing. CONCLUSIONS: The correlations of uteroglobin and FLRG with age in primary open angle glaucoma but not cataract may suggest a heightened requirement for anti-inflammatory (uteroglobin) or anti-calcification (FLRG) activity in the ageing glaucomatous trabecular meshwork.

Uteroglobin gene polymorphism (G38A) may be a risk factor in childhood idiopathic nephrotic syndrome.

BACKGROUND: Uteroglobin (UG) is a multifunctional protein with anti-inflammatory properties. The aim of this study was to first evaluate the role of UG gene G38A polymorphism in childhood idiopathic nephrotic syndrome (INS), and determine whether this variation may be related to the occurrence of INS or a steroid response. METHODS: One hundred and thirty-six children diagnosed with INS in Gaziantep University, Department of Pediatric Nephrology, and 70 healthy volunteers were included. Children with INS were divided into two groups: steroid-sensitive (n = 84), and steroid-resistant (n = 52). Samples were examined using the polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) enzyme method. RESULTS: The distributions of AA, GG, and AG genotypes of UG gene G38A (G/A) were 16.9%, 44.9%, and 38.2% in the all-INS group, whereas they were 14.3%, 48.8%, and 36.9% in the steroid-sensitive INS (SSINS) group compared with 21.1%, 38.5%, and 40.4% in steroid-resistant INS (SRINS), and 5.7%, 41.4%, and 52.9% in controls. The risk of INS was increased almost 4-fold in children with the AA genotype (p = 0.016). The risk of having SSINS was increased 3.5-fold (p = 0.042) whereas the risk of SRINS was increased 4.8-fold in the same genotype (p = 0.014). CONCLUSIONS: The uteroglobin gene may play an important role in the development of INS, and the AA genotype of UG gene G38A polymorphism was found more frequently in those children. Further studies evaluating all polymorphisms in larger patient groups are needed to exactly determine the effect of UG gene on the development of INS and steroid response in children.

Recombinant CC16 protein inhibits the production of pro-inflammatory cytokines via NF-κB and p38 MAPK pathways in LPS-activated RAW264.7 macrophages.

Accumulating evidence indicates that Clara cell protein-16 (CC16) has anti-inflammatory functions, although the involved molecular pathways have not been completely elucidated. Here, we evaluated the effect of recombinant rat CC16 (rCC16) on the expression of tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and IL-8 in lipopolysaccharide (LPS)-stimulated mouse macrophages (RAW264.7 cells) and explored the underlying molecular mechanisms. It was found that rCC16 inhibited LPS-induced TNF-α, IL-6, and IL-8 expression at both the messenger ribonucleicacid (mRNA) level and protein level in a concentration-dependent manner, as demonstrated by real-time reverse transcriptase-polymerase chain reaction and enzyme-linked immunosorbent assay. Such suppressive effects were accompanied by the inhibition of transcriptional activity and the deoxyribonucleic acid binding activity of nuclear factor (NF)-κB but not activator protein (AP)-1. Western blot analysis further revealed that rCC16 inhibited the increase of nuclear NF-κB and the reduction of cytosolic NF-κB, the phosphorylation and reduction of NF-κB inhibitory protein IκBα, and the p38 mitogen-activated protein kinase (MAPK)-dependent NF-κB activation by phosphorylation at Ser276 of its p65 subunit. Furthermore, rCC16 was found to have no effect on the phosphorylation of c-Jun N-terminal kinase, c-Jun, or the nuclear translocation of c-Jun. In addition, reduction of TNF-α, IL-6, and IL-8 were reversed when the level of endogenous uteroglobin-binding protein was reduced by RNA interference in rCC16- and LPS-treated RAW264.7 cells. Our data suggest that rCC16 suppresses LPS-mediated inflammatory mediator TNF-α, IL-6, and IL-8 production by inactivating NF-κB and p38 MAPK but not AP-1 in RAW264.7 cells.

Club Cell Protein 16 (CC16) Augmentation: A Potential Disease-modifying Approach for Chronic Obstructive Pulmonary Disease (COPD).

INTRODUCTION: Club cell protein 16 (CC16) is the most abundant protein in bronchoalveolar lavage fluid. CC16 has anti-inflammatory properties in smoke-exposed lungs, and chronic obstructive pulmonary disease (COPD) is associated with CC16 deficiency. Herein, we explored whether CC16 is a therapeutic target for COPD. AREAS COVERED: We reviewed the literature on the factors that regulate airway CC16 expression, its biologic functions and its protective activities in smoke-exposed lungs using PUBMED searches. We generated hypotheses on the mechanisms by which CC16 limits COPD development, and discuss its potential as a new therapeutic approach for COPD. EXPERT OPINION: CC16 plasma and lung levels are reduced in smokers without airflow obstruction and COPD patients. In COPD patients, airway CC16 expression is inversely correlated with severity of airflow obstruction. CC16 deficiency increases smoke-induced lung pathologies in mice by its effects on epithelial cells, leukocytes, and fibroblasts. Experimental augmentation of CC16 levels using recombinant CC16 in cell culture systems, plasmid and adenoviral-mediated over-expression of CC16 in epithelial cells or smoke-exposed murine airways reduces inflammation and cellular injury. Additional studies are necessary to assess the efficacy of therapies aimed at restoring airway CC16 levels as a new disease-modifying therapy for COPD patients.

Serum club cell protein 16 is associated with asymptomatic airway responsiveness in adults: Findings from the French epidemiological study on the genetics and environment of asthma.

BACKGROUND AND OBJECTIVE: Club cell secretory protein (CC-16) is a sensitive biomarker of airways epithelium integrity. It has gained interest as a biological marker in chronic lung diseases because of its presumed relationship to inflammation. Little is known about the association between CC-16 serum level and asthma, lung function and airway responsiveness (AR). METHODS: Serum CC-16 level was determined by latex immunoassay in 1298 participants from the French Epidemiological case-control and family-based study on Genetics and Environment of Asthma (EGEA) (mean age 43 years; 49% men, 38% with asthma). Pre-bronchodilator lung function (forced expiratory volume in 1 s (FEV1 ), forced vital capacity (FVC) and FEV1 /FVC) and degree of AR, expressed as a function of the dose-response slope to methacholine test were measured. Standardized residuals CC-16 z-scores were obtained by regressing CC-16 level on the glomerular filtration rate. CC-16 z-scores were correlated with asthma, lung function and AR in participants with and without asthma. RESULTS: CC-16 geometric mean level was 12.4 µg/L (range: 2.2-70.6 µg/L). In participants without asthma, lower CC-16 z-scores was associated with impaired FEV1 /FVC% (ß = 0.50 (95% CI: 0.06, 0.95) and with higher degree of AR (ß = 0.24 (95% CI: 0.09, 0.39)). CC-16 was not associated with impaired lung function or AR in participants with asthma. CONCLUSIONS: Lower CC-16 serum level was associated with impaired lung function and AR, suggesting that serum CC-16 level may reflect early damages to the lung epithelium in adults without asthma.

Association of uteroglobin G38A gene polymorphism with IgA nephropathy risk: an updated meta-analysis.

Association of uteroglobin G38A gene polymorphism and IgA nephropathy (IgAN) risk is still not clear. This investigation was conducted to assess if there was an association between the uteroglobin G38A gene polymorphism and IgAN risk using meta-analysis. The relevant literatures were identified from PubMed, and Cochrane Library on 10 October 2013, and eligible studies were included and synthesized. Seven reports were recruited into this meta-analysis for the association of the uteroglobin G38A gene polymorphism with IgAN risk. In overall population, the A allele and AA genotype were not associated with IgAN risk. Furthermore, the GG genotype was also not associated with IgAN risk in overall population. Interestingly, the association of uteroglobin G38A gene polymorphism with IgAN risk was also not found in Asians and in Caucasians. In the sensitivity analysis, according to Hardy-Weinberg equilibrium test, according to the control source from healthy, the genotyping methods using PCR-RFLP, PCR-SSCP, no association of the uteroglobin G38A gene polymorphism with IgAN risk was found and the results were similar to those in non-sensitivity analysis. In conclusion, the uteroglobin G38A gene polymorphism was not associated with IgAN risk. However, additional studies are required to firmly establish a correlation between the uteroglobin G38A gene polymorphism and IgAN risk.

Estrogen-regulated transcription of the uteroglobin gene from the brown hare (Lepus capensis).

To get further insights on the estrogen regulation of the uteroglobin (UG) gene, the 5'-flanking region of the UG gene from the brown hare (Lepus capensis) (Lc) was cloned and compared with those from two phylogenetically related species: the rabbit (Orictolagus cuniculus) (Oc) and the volcano rabbit (Romerolagus diazi) (Rd). The Lc-UG gene is very similar to those from rabbits (94%) and volcano rabbits (95%), and shares a number of genetic elements, including an estrogen response element (ERE). The estrogen-regulated transcription of a series of progressive 5'-deletion mutants of the Lc-UG gene, identified a functional ERE in the promoter region exhibiting the same orientation and relative position than that previously described in rabbits. The Lc-ERE is identical to the Oc-ERE, but different from both the Rd-ERE and the consensus ERE (c-ERE) by one nucleotide. We also detected important species-specific differences in the estrogen-regulated transcription of the UG gene. A luciferase reporter driven by 333 base pairs (bp) of the Lc-UG promoter elicited a higher response to estradiol than its related counterparts when expressed in estrogen-sensitive MCF-7 cells. Several ERE-like motifs which failed to act as functional EREs were also identified; one of them exhibited two mismatches in its palindromic sequence, a characteristic exhibited in many other natural occurring EREs, including the Rd-ERE.

Uteroglobin and the accumulation of progesterone in the uterine lumen of the rabbit.

This study was undertaken to determine whether the influx of progesterone into the uterine lumen of the rabbit, in the preimplantation period, is dependent onuteroglobin (UGL). Rabbits were ovariectomized and, three months later, treated with two defferent doses of progesterone. Purified UGL was injected into one uterine horn and, as a control,immunoglobulin G (IgG) was injected into the other. After four days, the animals were sacrificed their uteri flushed, and the progesterone content of the washes was determined by radioimmunoassay.Animals with the lower serum progesterone level (2.8 ng/ml) had a significantly different uterine horn progesterone content. The hormone accumulation in the horn containing UGL was 2.3 to 7.5 times higher than in the horn containing IgG. Animals with a higher serum progesterone level (7.2 ng/ml) showed no differences. The hormone content was equally high in both horns, presumably due to the synthesis of endogenous UGL being reactivated by the hormone treatment.The validity of these experiments as models for the events during early pregnancy and the physiological role of progesterone available inside the uterus are discussed.