Non-small cell lung cancer (NSCLC) accounts for 85% of all lung cancers. In NSCLC, 10-20% of Cauc... more Non-small cell lung cancer (NSCLC) accounts for 85% of all lung cancers. In NSCLC, 10-20% of Caucasian patients and 30-50% of Asian patients have tumors with activating mutations in the Epidermal Growth Factor Receptor (EGFR). A high percentage of these patients exhibit favorable responses to treatment with tyrosine kinase inhibitors (TKI). Unfortunately, a majority of these patients develop therapeutic resistance with progression free survival lasting 9- 18 months. The mechanisms that underlie the tumorigenic effects of EGFR and the ability of NSCLC to develop resistance to TKI therapies, however, are poorly understood. Here we demonstrate that CHI3L1 is produced by EGFR activation of normal epithelial cells, transformed epithelial cells with wild type EGFR and cells with cancer-associated, activating EGFR mutations. We also demonstrate that CHI3L1 auto-induces itself and feeds back to stimulate EGFR and its ligands. Highly specific antibodies against CHI3L1 (anti-CHI3L1/FRG) and T...
Chitinase is evolutionary conserved enzyme that participated to regulation of parasite life cycle... more Chitinase is evolutionary conserved enzyme that participated to regulation of parasite life cycle and anti-parasitic immune response. Chitinase like protein, which lack a chitinase activity by mutations of enzyme site also involved to anti-parasitic innate immunity, but their roles in T cell immunity has not been studied. Here, we investigated the role of mouse CLP BRP-39 in T cell immunity. BRP-39 is up-regulated in naïve CD4 T cell upon TcR stimuli. Although BRP-39-/- mouse does not have significant difference, BRP-39-/- T cells showed increased production of IL-2 and IFN-γ with hyper-proliferative response to TcR stimuli. In addition, BRP-39-/- naïve T cells more strongly differentiated into Th1 cells with up-regulated T-bet and Runx3 while their differentiation into Th2 was reduced with lower IL-4, 5 production and JunB expression. Also, pSTAT1, 4 were increased in BRP-39-/- Th1 cells while their Th2 cells showed lower pSTAT6 than WT. We found that expression of PTPN2, a phospha...
Chitinase‐3‐like protein 1 (CHI3L1/YKL‐40) has long been known as a biomarker for early detection... more Chitinase‐3‐like protein 1 (CHI3L1/YKL‐40) has long been known as a biomarker for early detection of neuroinflammation and disease diagnosis of Alzheimer's disease (AD). In the brain, CHI3L1 is primarily provided by astrocytes and heralds the reactive, neurotoxic state triggered by inflammation and other stress signals. However, how CHI3L1 acts in neuroinflammation or how it contributes to AD and relevant neurodegenerative conditions remains unknown. In peripheral tissues, our group and others have uncovered that CHI3L1 is a master regulator for a wide range of injury and repair events, including the innate immunity pathway that resembles the neuroinflammation process governed by microglia and astrocytes. Based on assessment of current knowledge regarding CHI3L1 biology, we hypothesize that CHI3L1 functions as a signaling molecule mediating distinct neuroinflammatory responses in brain cells and misfunctions to precipitate neurodegeneration. We also recommend future research dir...
Background: Recent attempts to develop more efficacious treatments for asthma, a TH2-dominant dis... more Background: Recent attempts to develop more efficacious treatments for asthma, a TH2-dominant disease, have incorporated mesenchymal stem cell (MSC)-based cell therapies. Despite numerous previous studies, the full action mechanism of the pathogenesis of asthma remains undiscovered, and the need for further investigation is increasing in order to identify more effective target molecules. Objective: This study aimed to evaluate the anti-asthmatic effects of intratracheally administered MSCs primed with Liproxstatin-1, a potent ferroptosis inhibitor. In addition, we sought to examine the changes within macrophage populations and their characteristics in asthmatic conditions to explain the pathogenesis of asthma. Methods: Seven-week-old transgenic (TG) mice, constitutively overexpressing lung-specific interleukin (IL)-13, were used to simulate chronic asthma. Human umbilical cord-derived MSCs (hUC-MSCs) primed with Liproxstatin-1 were intratracheally administered four days prior to sam...
IMPORTANCE Incentive spirometers (ISs) were developed to reduce atelectasis and are in widespread... more IMPORTANCE Incentive spirometers (ISs) were developed to reduce atelectasis and are in widespread clinical use. However, without IS use adherence data, the effectiveness of IS cannot be determined. OBJECTIVE To evaluate the effect of a use-tracking IS reminder on patient adherence and clinical outcomes following coronary artery bypass grafting (CABG) surgery. DESIGN, SETTING, AND PARTICIPANTS This randomized clinical trial was conducted from June 5, 2017, to December 29, 2017, at a tertiary referral teaching hospital and included 212 patients who underwent CABG, of whom 160 participants were randomized (intent to treat), with 145 completing the study per protocol. Participants were stratified by surgical urgency (elective vs nonelective) and sex (men vs women). INTERVENTIONS A use-tracking, IS add-on device (SpiroTimer) with an integrated use reminder bell recorded and timestamped participants' inspiratory breaths. Patients were randomized by hourly reminder "bell on" (experimental group) or "bell off" (control group). MAIN OUTCOMES AND MEASURES Incentive spirometer use was recorded for the entire postoperative stay and compared between groups. Radiographic atelectasis severity (score, 0-10) was the primary clinical outcome. Secondary respiratory and nonrespiratory outcomes were also evaluated. RESULTS A total of 145 per-protocol participants (112 men [77%]; mean age, 69 years [95% CI, 67-70]; 90 [62%] undergoing a nonelective procedure) were evaluated, with 74 (51.0%) in the bell off group and 71 (49.0%) in the bell on group. The baseline medical and motivation-torecover characteristics of the 2 groups were similar. The mean number of daily inspiratory breaths was greater in bell on (35; 95% CI, 29-43 vs 17; 95% CI, 13-23; P < .001). The percentage of recorded hours with an inspiratory breath event was greater in bell on (58%; 95% CI, 51-65 vs 28%; 95% CI, 23-32; P < .001). Despite no differences in the first postoperative chest radiograph mean atelectasis severity scores (2.3; 95% CI, 2.0-2.6 vs 2.4; 95% CI, 2.2-2.7; P = .48), the mean atelectasis severity scores for the final chest radiographs conducted before discharge were significantly lower for bell on than bell off group (1.5; 95% CI, 1.3-1.8 vs 1.8; 95% CI, 1.6-2.1; P = .04). Of those with early postoperative fevers, fever duration was shorter for bell on (3.2 hours; 95% CI, 2.3-4.6 vs 5.2 hours; 95% CI, 3.9-7.0; P = .04). Having the bell turned on reduced noninvasive positive pressure ventilation use rates (37.2%; 95% CI, 24.1%-52.5% vs 19.2%; 95% CI, 10.2%-33.0%; P = .03) for participants undergoing nonelective procedures. Bell on reduced the median postoperative length of stay (7 days; 95% CI, 6-9 vs 6 days; 95% CI, 6-7; P = .048) and the intensive care unit length of stay for patients undergoing nonelective procedures (4 days; 95% CI, 3-5 vs 3 days; 95% CI, 3-4; P = .02). At 6 months, the bell off mortality rate was higher than bell on (9% vs 0%, P = .048) for participants undergoing nonelective procedures. CONCLUSIONS AND RELEVANCE The incentive spirometer reminder improved patient adherence, atelectasis severity, early postoperative fever duration, noninvasive positive pressure ventilation use, ICU and length of stay, and 6-month mortality in certain patients. With the reminder, IS appears to be clinically effective when used appropriately.
Exaggerated Type 2 immune responses play critical roles in the pathogenesis of a variety of disea... more Exaggerated Type 2 immune responses play critical roles in the pathogenesis of a variety of diseases including asthma, allergy, and pulmonary fibrosis. Recent studies have highlighted the importance of innate type 2 immune responses and innate lymphoid 2 cells (ILC2s) in these disorders. However, the mechanisms that control the development of pulmonary innate type 2 responses (IT2IR) and the recruitment and/or activation of ILC2 cells are poorly understood. In mouse models of pulmonary IT2IR, we demonstrated that Phospholipid scramblase-1 (PLSCR1), a type II transmembrane protein that mediates bidirectional and non-specific translocation of phospholipids between the inner and outer leaflets of the plasma membrane, was a critical regulator of IT2IR in the lung. We further suggested that PLSCR1 bound to and physically interacted with CRTH2 (Chemoattractant receptor-homologous molecule expressed on TH2 cells), a G-proteincoupled receptor that is expressed on multiple immune cells and commonly used to identify ILC2 cells, and the effects of PLSCR1 on ILC2 activation and IT2IR were mediated via CRTH2dependent mechanisms. Overall, our studies demonstrated that PLSCR1 played an essential role in the pathogenesis of ILC2 responses, providing critical insights into biology and disease pathogenesis and identifying targets that can be manipulated in attempts to control IT2IR in chronic diseases such as asthma.
Acidic mammalian chitinase (AMCase) is expressed in an exaggerated fashion in epithelial cells at... more Acidic mammalian chitinase (AMCase) is expressed in an exaggerated fashion in epithelial cells at sites of pulmonary T helper cell type 2 inflammation and plays important roles in the pathogenesis of anti-parasite and asthma-like responses. However, the mechanisms that control epithelial cell AMCase secretion and its effector responses have not been adequately defined. To address these issues, we used in vivo and in vitro experimental systems to define the pathways of epithelial AMCase secretion and its epithelial regulatory effects. Here we demonstrate that, in murine T helper cell type 2 modeling systems, AMCase colocalizes with the epidermal growth factor receptor (EGFR) and ADAM17 (a membrane disintegrin and metallopeptidase 17) in lung epithelial cells. In vitro cotransfection experiments in A549 cells demonstrated that AMCase and EGFR physically interact with each other. Cotransfection of AMCase and EGFR also increased, whereas EGFR inhibition decreased AMCase secretion. Interestingly, AMCase secretion was not significantly altered by treatment with EGF but was significantly decreased when the upstream EGFR transactivator ADAM17 was inhibited. AMCase secretion was also decreased when the EGFR-downstream Ras was blocked. Transfected and recombinant AMCase induced epithelial cell production of CCL2, CCL17, and CXCL8. These studies demonstrate that lung epithelial cells secrete AMCase via an EGFR-dependent pathway that is activated by ADAM17 and mediates its effects via Ras. They also demonstrate that the AMCase that is secreted feeds back in an autocrine and/or paracrine fashion to stimulate pulmonary epithelial cell chemokine production.
Journal of The American Society of Nephrology, Jan 4, 2013
Kidney hypoperfusion during episodes of systemic hypotension or after surgical procurement for tr... more Kidney hypoperfusion during episodes of systemic hypotension or after surgical procurement for transplantation can lead to tubular cell death via necrosis and apoptosis, which trigger a series of responses that promote repair. The factors that contribute to the repair phase after kidney injury are not well understood. Using a urine proteomic screen in mice, we identified the macrophage-secreted chitinase-like protein Brp-39, the murine protein product of the chitinase 3-like 1 gene, as a critical component of this reparative response that serves to limit tubular cell apoptotic death via activation of Akt, improving animal survival after kidney ischemia/reperfusion. Examination of graded times of renal ischemia revealed a direct correlation between the degree of kidney injury and both Chi3l1/Brp-39 expression in the kidney and its levels in the urine. In samples collected from patients undergoing deceased-donor kidney transplantation, we found higher levels of the orthologous human protein, YKL-40, in urine and blood from allografts subjected to sufficient peri-transplant ischemia to cause delayed graft function than from allografts with slow or immediate graft function. Urinary levels of YKL-40 obtained within hours of transplant predicted the need for subsequent dialysis in these patients. In summary, these data suggest that Brp-39/YKL-40 is a sensor of the degree of injury, a critical mediator of the reparative response, and a possible biomarker to identify patients at greatest risk of sustained renal failure after transplantation.
The 18 glycosyl hydrolase family of chitinases is an ancient gene family that is widely expressed... more The 18 glycosyl hydrolase family of chitinases is an ancient gene family that is widely expressed from prokaryotes to eukaryotes. In mammals, despite the absence of endogenous chitin, a number of chitinases and chitinase-like proteins (C/CLPs) have been identified. However, their roles have only recently begun to be elucidated. Acidic mammalian chitinase (AMCase) inhibits chitininduced innate inflammation; augments chitin-free, allergen-induced Th2 inflammation; and mediates effector functions of IL-13. The CLPs BRP-39/YKL-40 (also termed chitinase 3-like 1) inhibit oxidant-induced lung injury, augments adaptive Th2 immunity, regulates apoptosis, stimulates alternative macrophage activation, and contributes to fibrosis and wound healing. In accord with these findings, levels of YKL-40 in the lung and serum are increased in asthma and other inflammatory and remodeling disorders and often correlate with disease severity. Our understanding of the roles of C/CLPs in inflammation, tissue remodeling, and tissue injury in health and disease is reviewed below.
One of the most exciting breakthroughs in the cancer field is the discovery of immune checkpoint ... more One of the most exciting breakthroughs in the cancer field is the discovery of immune checkpoint molecules (ICPs) such as PD-1 and its ligands PD-L1 and PD-L2 as an immune evasion mechanism for cancer cells. Although the immunotherapeutics targeting ICPs have great success in many tumors, including lung cancer, still the response rates are very limited. Thus, understanding the underlying regulatory mechanism for these molecules is essential to develop rational and new immunotherapeutic strategies to maximize the clinical outcomes for patients. Chitinase 3-like-1, as a proinflammatory and protumorigenic molecule, has increased expression in many solid tumors including lung cancer. Circulating levels of Chi3l1 are also highly correlated with poor prognosis and decreased survival rates. However, the specific role of Chi3l1 in tumor initiation and progression and as an immunomodulator in the pulmonary tumor microenvironment has not been adequately defined. Recently we have discovered that melanoma lung metastasis was significantly reduced in Chi3l1 null mutant (Brp39−/−) mice and the mice treated with anti-Chi3l1 antibody (FRG) while it was increased in overexpressing transgenic mice (YKL-40 Tg) compared to the controls, suggesting a critical role of Chi3l1 in metastatic spread and colonization. We also showed that Chi3l1 transgene expression leads to infiltration of immune cells, particularly myeloid cells into the lung, and causes dysregulated expression of PD-L1 on the macrophages. In vitro studies by using bone marrow-derived macrophages demonstrated a blunted IFNg induced PD-L1 expressions in Brp39−/− cells compared to WT controls. Additionally, we have found that the FRG antibody has synergizing effect on anti-PD1 treatment in metastatic lung cancer model. FRG antibody treatment can also effectively inhibit tumor development and also promotes CD8+ T-cell infiltration into the tumor area compared to control treatment in primary lung cancer model (K-ras+/G12D/ P53−/−mice). Overall, our studies demonstrated that Chi3l1 plays an important role in lung cancer development or progression through regulating PD-1/PD-L1/L2 axis and T-cell infiltration. These studies also highlight a significant therapeutic potential of FRG antibody for lung cancer as a single or combinational immunotherapeutic agent. Citation Format: Bedia Akosman, Bing Ma, Suchitra Kamle, Dilara Kurtulus, Chang-Min Lee, Chun Lee, Jack Elias. Chitinase-3-like-1: A new immunomodulatory target in lung cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr A71.
Members of the 18 glycosyl hydrolase (GH 18) gene family have been conserved over species and tim... more Members of the 18 glycosyl hydrolase (GH 18) gene family have been conserved over species and time and are dysregulated in inflammatory, infectious, remodeling, and neoplastic disorders. This is particularly striking for the prototypic chitinase-like protein chitinase 3-like 1 (Chi3l1), which plays a critical role in antipathogen responses where it augments bacterial killing while stimulating disease tolerance by controlling cell death, inflammation, and remodeling. However, receptors that mediate the effects of GH 18 moieties have not been defined. Here, we demonstrate that Chi3l1 binds to interleukin-13 receptor α2 (IL-13Rα2) and that Chi3l1, IL-13Rα2, and IL-13 are in a multimeric complex. We also demonstrate that Chi3l1 activates macrophage mitogen-activated protein kinase, protein kinase B/AKT, and Wnt/β-catenin signaling and regulates oxidant injury, apoptosis, pyroptosis, inflammasome activation, antibacterial responses, melanoma metastasis, and TGF-β1 production via IL-13Rα2-dependent mechanisms. Thus, IL-13Rα2 is a GH 18 receptor that plays a critical role in Chi3l1 effector responses.
Host antibacterial responses include mechanisms that kill bacteria, but also those that protect o... more Host antibacterial responses include mechanisms that kill bacteria, but also those that protect or tolerize the host to potentially damaging antibacterial effects. We determined that Chitinase 3-like-1 (Chi3l1), a conserved prototypic chitinase-like protein, is induced by Streptococcus pneumoniae and plays central roles in promoting bacterial clearance and mediating host tolerance. S. pneumoniaeinfected Chi3l1 null mice exhibit exaggerated lung injury, inflammation and hemorrhage, more frequent bacterial dissemination, decreased bacterial clearance, and enhanced mortality compared to controls. Chi3l1 augments macrophage bacterial killing by inhibiting caspase-1-dependent macrophage pyroptosis and augments host tolerance by controlling inflammasome activation, ATP accumulation, expression of ATP receptor P2X7R, and production of thymic stromal lymphopoietin and type 1, type 2, and type 17 cytokines. These data demonstrate that Chi3l1 is induced during infection, where it promotes bacterial clearance while simultaneously augmenting host tolerance, and that these roles likely contributed to the retention of Chi3l1 over species and evolutionary time.
Recent studies demonstrated that chitinase 3-like-1 (Chi3l1) binds to and signals via IL-13Ra2. H... more Recent studies demonstrated that chitinase 3-like-1 (Chi3l1) binds to and signals via IL-13Ra2. However, the mechanism that IL-13Ra2 uses to mediate the effects of Chi3l1 has not been defined. Here, we demonstrate that the membrane protein, TMEM219, is a binding partner of IL-13Ra2 using yeast two-hybrid, co-immunoprecipitation, co-localization and bimolecular fluorescence complementation assays. Furthermore, fluorescence anisotropy nanodisc assays revealed a direct physical interaction between TMEM219 and IL-13Ra2-Chi3l1 complexes. Null mutations or siRNA silencing of TMEM219 or IL-13Ra2 similarly decreased Chi3l1-stimulated epithelial cell HB-EGF production and macrophage MAPK/Erk and PKB/Akt activation. Null mutations of TMEM219 or IL-13Ra2 also phenocopied one another as regards the ability of Chi3l1 to inhibit oxidant-induced apoptosis and lung injury, promote melanoma metastasis and stimulate TGF-b1. TMEM219 also contributed to the decoy function of IL-13Ra2. These studies demonstrate that TMEM219 plays a critical role in Chi3l1-induced IL-13Ra2 mediated signalling and tissue responses.
Non-small cell lung cancer (NSCLC) accounts for 85% of all lung cancers. In NSCLC, 10-20% of Cauc... more Non-small cell lung cancer (NSCLC) accounts for 85% of all lung cancers. In NSCLC, 10-20% of Caucasian patients and 30-50% of Asian patients have tumors with activating mutations in the Epidermal Growth Factor Receptor (EGFR). A high percentage of these patients exhibit favorable responses to treatment with tyrosine kinase inhibitors (TKI). Unfortunately, a majority of these patients develop therapeutic resistance with progression free survival lasting 9- 18 months. The mechanisms that underlie the tumorigenic effects of EGFR and the ability of NSCLC to develop resistance to TKI therapies, however, are poorly understood. Here we demonstrate that CHI3L1 is produced by EGFR activation of normal epithelial cells, transformed epithelial cells with wild type EGFR and cells with cancer-associated, activating EGFR mutations. We also demonstrate that CHI3L1 auto-induces itself and feeds back to stimulate EGFR and its ligands. Highly specific antibodies against CHI3L1 (anti-CHI3L1/FRG) and T...
Chitinase is evolutionary conserved enzyme that participated to regulation of parasite life cycle... more Chitinase is evolutionary conserved enzyme that participated to regulation of parasite life cycle and anti-parasitic immune response. Chitinase like protein, which lack a chitinase activity by mutations of enzyme site also involved to anti-parasitic innate immunity, but their roles in T cell immunity has not been studied. Here, we investigated the role of mouse CLP BRP-39 in T cell immunity. BRP-39 is up-regulated in naïve CD4 T cell upon TcR stimuli. Although BRP-39-/- mouse does not have significant difference, BRP-39-/- T cells showed increased production of IL-2 and IFN-γ with hyper-proliferative response to TcR stimuli. In addition, BRP-39-/- naïve T cells more strongly differentiated into Th1 cells with up-regulated T-bet and Runx3 while their differentiation into Th2 was reduced with lower IL-4, 5 production and JunB expression. Also, pSTAT1, 4 were increased in BRP-39-/- Th1 cells while their Th2 cells showed lower pSTAT6 than WT. We found that expression of PTPN2, a phospha...
Chitinase‐3‐like protein 1 (CHI3L1/YKL‐40) has long been known as a biomarker for early detection... more Chitinase‐3‐like protein 1 (CHI3L1/YKL‐40) has long been known as a biomarker for early detection of neuroinflammation and disease diagnosis of Alzheimer's disease (AD). In the brain, CHI3L1 is primarily provided by astrocytes and heralds the reactive, neurotoxic state triggered by inflammation and other stress signals. However, how CHI3L1 acts in neuroinflammation or how it contributes to AD and relevant neurodegenerative conditions remains unknown. In peripheral tissues, our group and others have uncovered that CHI3L1 is a master regulator for a wide range of injury and repair events, including the innate immunity pathway that resembles the neuroinflammation process governed by microglia and astrocytes. Based on assessment of current knowledge regarding CHI3L1 biology, we hypothesize that CHI3L1 functions as a signaling molecule mediating distinct neuroinflammatory responses in brain cells and misfunctions to precipitate neurodegeneration. We also recommend future research dir...
Background: Recent attempts to develop more efficacious treatments for asthma, a TH2-dominant dis... more Background: Recent attempts to develop more efficacious treatments for asthma, a TH2-dominant disease, have incorporated mesenchymal stem cell (MSC)-based cell therapies. Despite numerous previous studies, the full action mechanism of the pathogenesis of asthma remains undiscovered, and the need for further investigation is increasing in order to identify more effective target molecules. Objective: This study aimed to evaluate the anti-asthmatic effects of intratracheally administered MSCs primed with Liproxstatin-1, a potent ferroptosis inhibitor. In addition, we sought to examine the changes within macrophage populations and their characteristics in asthmatic conditions to explain the pathogenesis of asthma. Methods: Seven-week-old transgenic (TG) mice, constitutively overexpressing lung-specific interleukin (IL)-13, were used to simulate chronic asthma. Human umbilical cord-derived MSCs (hUC-MSCs) primed with Liproxstatin-1 were intratracheally administered four days prior to sam...
IMPORTANCE Incentive spirometers (ISs) were developed to reduce atelectasis and are in widespread... more IMPORTANCE Incentive spirometers (ISs) were developed to reduce atelectasis and are in widespread clinical use. However, without IS use adherence data, the effectiveness of IS cannot be determined. OBJECTIVE To evaluate the effect of a use-tracking IS reminder on patient adherence and clinical outcomes following coronary artery bypass grafting (CABG) surgery. DESIGN, SETTING, AND PARTICIPANTS This randomized clinical trial was conducted from June 5, 2017, to December 29, 2017, at a tertiary referral teaching hospital and included 212 patients who underwent CABG, of whom 160 participants were randomized (intent to treat), with 145 completing the study per protocol. Participants were stratified by surgical urgency (elective vs nonelective) and sex (men vs women). INTERVENTIONS A use-tracking, IS add-on device (SpiroTimer) with an integrated use reminder bell recorded and timestamped participants' inspiratory breaths. Patients were randomized by hourly reminder "bell on" (experimental group) or "bell off" (control group). MAIN OUTCOMES AND MEASURES Incentive spirometer use was recorded for the entire postoperative stay and compared between groups. Radiographic atelectasis severity (score, 0-10) was the primary clinical outcome. Secondary respiratory and nonrespiratory outcomes were also evaluated. RESULTS A total of 145 per-protocol participants (112 men [77%]; mean age, 69 years [95% CI, 67-70]; 90 [62%] undergoing a nonelective procedure) were evaluated, with 74 (51.0%) in the bell off group and 71 (49.0%) in the bell on group. The baseline medical and motivation-torecover characteristics of the 2 groups were similar. The mean number of daily inspiratory breaths was greater in bell on (35; 95% CI, 29-43 vs 17; 95% CI, 13-23; P < .001). The percentage of recorded hours with an inspiratory breath event was greater in bell on (58%; 95% CI, 51-65 vs 28%; 95% CI, 23-32; P < .001). Despite no differences in the first postoperative chest radiograph mean atelectasis severity scores (2.3; 95% CI, 2.0-2.6 vs 2.4; 95% CI, 2.2-2.7; P = .48), the mean atelectasis severity scores for the final chest radiographs conducted before discharge were significantly lower for bell on than bell off group (1.5; 95% CI, 1.3-1.8 vs 1.8; 95% CI, 1.6-2.1; P = .04). Of those with early postoperative fevers, fever duration was shorter for bell on (3.2 hours; 95% CI, 2.3-4.6 vs 5.2 hours; 95% CI, 3.9-7.0; P = .04). Having the bell turned on reduced noninvasive positive pressure ventilation use rates (37.2%; 95% CI, 24.1%-52.5% vs 19.2%; 95% CI, 10.2%-33.0%; P = .03) for participants undergoing nonelective procedures. Bell on reduced the median postoperative length of stay (7 days; 95% CI, 6-9 vs 6 days; 95% CI, 6-7; P = .048) and the intensive care unit length of stay for patients undergoing nonelective procedures (4 days; 95% CI, 3-5 vs 3 days; 95% CI, 3-4; P = .02). At 6 months, the bell off mortality rate was higher than bell on (9% vs 0%, P = .048) for participants undergoing nonelective procedures. CONCLUSIONS AND RELEVANCE The incentive spirometer reminder improved patient adherence, atelectasis severity, early postoperative fever duration, noninvasive positive pressure ventilation use, ICU and length of stay, and 6-month mortality in certain patients. With the reminder, IS appears to be clinically effective when used appropriately.
Exaggerated Type 2 immune responses play critical roles in the pathogenesis of a variety of disea... more Exaggerated Type 2 immune responses play critical roles in the pathogenesis of a variety of diseases including asthma, allergy, and pulmonary fibrosis. Recent studies have highlighted the importance of innate type 2 immune responses and innate lymphoid 2 cells (ILC2s) in these disorders. However, the mechanisms that control the development of pulmonary innate type 2 responses (IT2IR) and the recruitment and/or activation of ILC2 cells are poorly understood. In mouse models of pulmonary IT2IR, we demonstrated that Phospholipid scramblase-1 (PLSCR1), a type II transmembrane protein that mediates bidirectional and non-specific translocation of phospholipids between the inner and outer leaflets of the plasma membrane, was a critical regulator of IT2IR in the lung. We further suggested that PLSCR1 bound to and physically interacted with CRTH2 (Chemoattractant receptor-homologous molecule expressed on TH2 cells), a G-proteincoupled receptor that is expressed on multiple immune cells and commonly used to identify ILC2 cells, and the effects of PLSCR1 on ILC2 activation and IT2IR were mediated via CRTH2dependent mechanisms. Overall, our studies demonstrated that PLSCR1 played an essential role in the pathogenesis of ILC2 responses, providing critical insights into biology and disease pathogenesis and identifying targets that can be manipulated in attempts to control IT2IR in chronic diseases such as asthma.
Acidic mammalian chitinase (AMCase) is expressed in an exaggerated fashion in epithelial cells at... more Acidic mammalian chitinase (AMCase) is expressed in an exaggerated fashion in epithelial cells at sites of pulmonary T helper cell type 2 inflammation and plays important roles in the pathogenesis of anti-parasite and asthma-like responses. However, the mechanisms that control epithelial cell AMCase secretion and its effector responses have not been adequately defined. To address these issues, we used in vivo and in vitro experimental systems to define the pathways of epithelial AMCase secretion and its epithelial regulatory effects. Here we demonstrate that, in murine T helper cell type 2 modeling systems, AMCase colocalizes with the epidermal growth factor receptor (EGFR) and ADAM17 (a membrane disintegrin and metallopeptidase 17) in lung epithelial cells. In vitro cotransfection experiments in A549 cells demonstrated that AMCase and EGFR physically interact with each other. Cotransfection of AMCase and EGFR also increased, whereas EGFR inhibition decreased AMCase secretion. Interestingly, AMCase secretion was not significantly altered by treatment with EGF but was significantly decreased when the upstream EGFR transactivator ADAM17 was inhibited. AMCase secretion was also decreased when the EGFR-downstream Ras was blocked. Transfected and recombinant AMCase induced epithelial cell production of CCL2, CCL17, and CXCL8. These studies demonstrate that lung epithelial cells secrete AMCase via an EGFR-dependent pathway that is activated by ADAM17 and mediates its effects via Ras. They also demonstrate that the AMCase that is secreted feeds back in an autocrine and/or paracrine fashion to stimulate pulmonary epithelial cell chemokine production.
Journal of The American Society of Nephrology, Jan 4, 2013
Kidney hypoperfusion during episodes of systemic hypotension or after surgical procurement for tr... more Kidney hypoperfusion during episodes of systemic hypotension or after surgical procurement for transplantation can lead to tubular cell death via necrosis and apoptosis, which trigger a series of responses that promote repair. The factors that contribute to the repair phase after kidney injury are not well understood. Using a urine proteomic screen in mice, we identified the macrophage-secreted chitinase-like protein Brp-39, the murine protein product of the chitinase 3-like 1 gene, as a critical component of this reparative response that serves to limit tubular cell apoptotic death via activation of Akt, improving animal survival after kidney ischemia/reperfusion. Examination of graded times of renal ischemia revealed a direct correlation between the degree of kidney injury and both Chi3l1/Brp-39 expression in the kidney and its levels in the urine. In samples collected from patients undergoing deceased-donor kidney transplantation, we found higher levels of the orthologous human protein, YKL-40, in urine and blood from allografts subjected to sufficient peri-transplant ischemia to cause delayed graft function than from allografts with slow or immediate graft function. Urinary levels of YKL-40 obtained within hours of transplant predicted the need for subsequent dialysis in these patients. In summary, these data suggest that Brp-39/YKL-40 is a sensor of the degree of injury, a critical mediator of the reparative response, and a possible biomarker to identify patients at greatest risk of sustained renal failure after transplantation.
The 18 glycosyl hydrolase family of chitinases is an ancient gene family that is widely expressed... more The 18 glycosyl hydrolase family of chitinases is an ancient gene family that is widely expressed from prokaryotes to eukaryotes. In mammals, despite the absence of endogenous chitin, a number of chitinases and chitinase-like proteins (C/CLPs) have been identified. However, their roles have only recently begun to be elucidated. Acidic mammalian chitinase (AMCase) inhibits chitininduced innate inflammation; augments chitin-free, allergen-induced Th2 inflammation; and mediates effector functions of IL-13. The CLPs BRP-39/YKL-40 (also termed chitinase 3-like 1) inhibit oxidant-induced lung injury, augments adaptive Th2 immunity, regulates apoptosis, stimulates alternative macrophage activation, and contributes to fibrosis and wound healing. In accord with these findings, levels of YKL-40 in the lung and serum are increased in asthma and other inflammatory and remodeling disorders and often correlate with disease severity. Our understanding of the roles of C/CLPs in inflammation, tissue remodeling, and tissue injury in health and disease is reviewed below.
One of the most exciting breakthroughs in the cancer field is the discovery of immune checkpoint ... more One of the most exciting breakthroughs in the cancer field is the discovery of immune checkpoint molecules (ICPs) such as PD-1 and its ligands PD-L1 and PD-L2 as an immune evasion mechanism for cancer cells. Although the immunotherapeutics targeting ICPs have great success in many tumors, including lung cancer, still the response rates are very limited. Thus, understanding the underlying regulatory mechanism for these molecules is essential to develop rational and new immunotherapeutic strategies to maximize the clinical outcomes for patients. Chitinase 3-like-1, as a proinflammatory and protumorigenic molecule, has increased expression in many solid tumors including lung cancer. Circulating levels of Chi3l1 are also highly correlated with poor prognosis and decreased survival rates. However, the specific role of Chi3l1 in tumor initiation and progression and as an immunomodulator in the pulmonary tumor microenvironment has not been adequately defined. Recently we have discovered that melanoma lung metastasis was significantly reduced in Chi3l1 null mutant (Brp39−/−) mice and the mice treated with anti-Chi3l1 antibody (FRG) while it was increased in overexpressing transgenic mice (YKL-40 Tg) compared to the controls, suggesting a critical role of Chi3l1 in metastatic spread and colonization. We also showed that Chi3l1 transgene expression leads to infiltration of immune cells, particularly myeloid cells into the lung, and causes dysregulated expression of PD-L1 on the macrophages. In vitro studies by using bone marrow-derived macrophages demonstrated a blunted IFNg induced PD-L1 expressions in Brp39−/− cells compared to WT controls. Additionally, we have found that the FRG antibody has synergizing effect on anti-PD1 treatment in metastatic lung cancer model. FRG antibody treatment can also effectively inhibit tumor development and also promotes CD8+ T-cell infiltration into the tumor area compared to control treatment in primary lung cancer model (K-ras+/G12D/ P53−/−mice). Overall, our studies demonstrated that Chi3l1 plays an important role in lung cancer development or progression through regulating PD-1/PD-L1/L2 axis and T-cell infiltration. These studies also highlight a significant therapeutic potential of FRG antibody for lung cancer as a single or combinational immunotherapeutic agent. Citation Format: Bedia Akosman, Bing Ma, Suchitra Kamle, Dilara Kurtulus, Chang-Min Lee, Chun Lee, Jack Elias. Chitinase-3-like-1: A new immunomodulatory target in lung cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr A71.
Members of the 18 glycosyl hydrolase (GH 18) gene family have been conserved over species and tim... more Members of the 18 glycosyl hydrolase (GH 18) gene family have been conserved over species and time and are dysregulated in inflammatory, infectious, remodeling, and neoplastic disorders. This is particularly striking for the prototypic chitinase-like protein chitinase 3-like 1 (Chi3l1), which plays a critical role in antipathogen responses where it augments bacterial killing while stimulating disease tolerance by controlling cell death, inflammation, and remodeling. However, receptors that mediate the effects of GH 18 moieties have not been defined. Here, we demonstrate that Chi3l1 binds to interleukin-13 receptor α2 (IL-13Rα2) and that Chi3l1, IL-13Rα2, and IL-13 are in a multimeric complex. We also demonstrate that Chi3l1 activates macrophage mitogen-activated protein kinase, protein kinase B/AKT, and Wnt/β-catenin signaling and regulates oxidant injury, apoptosis, pyroptosis, inflammasome activation, antibacterial responses, melanoma metastasis, and TGF-β1 production via IL-13Rα2-dependent mechanisms. Thus, IL-13Rα2 is a GH 18 receptor that plays a critical role in Chi3l1 effector responses.
Host antibacterial responses include mechanisms that kill bacteria, but also those that protect o... more Host antibacterial responses include mechanisms that kill bacteria, but also those that protect or tolerize the host to potentially damaging antibacterial effects. We determined that Chitinase 3-like-1 (Chi3l1), a conserved prototypic chitinase-like protein, is induced by Streptococcus pneumoniae and plays central roles in promoting bacterial clearance and mediating host tolerance. S. pneumoniaeinfected Chi3l1 null mice exhibit exaggerated lung injury, inflammation and hemorrhage, more frequent bacterial dissemination, decreased bacterial clearance, and enhanced mortality compared to controls. Chi3l1 augments macrophage bacterial killing by inhibiting caspase-1-dependent macrophage pyroptosis and augments host tolerance by controlling inflammasome activation, ATP accumulation, expression of ATP receptor P2X7R, and production of thymic stromal lymphopoietin and type 1, type 2, and type 17 cytokines. These data demonstrate that Chi3l1 is induced during infection, where it promotes bacterial clearance while simultaneously augmenting host tolerance, and that these roles likely contributed to the retention of Chi3l1 over species and evolutionary time.
Recent studies demonstrated that chitinase 3-like-1 (Chi3l1) binds to and signals via IL-13Ra2. H... more Recent studies demonstrated that chitinase 3-like-1 (Chi3l1) binds to and signals via IL-13Ra2. However, the mechanism that IL-13Ra2 uses to mediate the effects of Chi3l1 has not been defined. Here, we demonstrate that the membrane protein, TMEM219, is a binding partner of IL-13Ra2 using yeast two-hybrid, co-immunoprecipitation, co-localization and bimolecular fluorescence complementation assays. Furthermore, fluorescence anisotropy nanodisc assays revealed a direct physical interaction between TMEM219 and IL-13Ra2-Chi3l1 complexes. Null mutations or siRNA silencing of TMEM219 or IL-13Ra2 similarly decreased Chi3l1-stimulated epithelial cell HB-EGF production and macrophage MAPK/Erk and PKB/Akt activation. Null mutations of TMEM219 or IL-13Ra2 also phenocopied one another as regards the ability of Chi3l1 to inhibit oxidant-induced apoptosis and lung injury, promote melanoma metastasis and stimulate TGF-b1. TMEM219 also contributed to the decoy function of IL-13Ra2. These studies demonstrate that TMEM219 plays a critical role in Chi3l1-induced IL-13Ra2 mediated signalling and tissue responses.
Uploads
Papers by Jack a. Elias