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504 results on '"Pilewski, Joseph M."'

3. Type‐1 immunity and endogenous immune regulators predominate in the airway transcriptome during chronic lung allograft dysfunction

Author

Iasella, Carlo J, Hoji, Aki, Popescu, Iulia, Wei, Jianxin, Snyder, Mark E, Zhang, Yingze, Xu, Wei, Iouchmanov, Vera, Koshy, Ritchie, Brown, Mark, Fung, Monica, Langelier, Charles, Lendermon, Elizabeth A, Dugger, Daniel, Shah, Rupal, Lee, Joyce, Johnson, Bruce, Golden, Jeffrey, Leard, Lorriana E, Kleinhenz, Mary Ellen, Kilaru, Silpa, Hays, Steven R, Singer, Jonathan P, Sanchez, Pablo G, Morrell, Matthew R, Pilewski, Joseph M, Greenland, John R, Chen, Kong, and McDyer, John F

Subjects
Biomedical and Clinical Sciences, Immunology, Transplantation, Clinical Research, Prevention, Lung, Genetics, Detection, screening and diagnosis, 4.1 Discovery and preclinical testing of markers and technologies, 2.1 Biological and endogenous factors, Aetiology, Respiratory, Allografts, Bronchiolitis Obliterans, Graft Rejection, Humans, Lung Transplantation, Proteomics, Transcriptome, biomarker, bronchiolitis obliterans, clinical research, practice, immune regulation, immunobiology, lung (allograft) function, dysfunction, lung transplantation, pulmonology, molecular biology, mRNA, mRNA expression, clinical research / practice, lung (allograft) function / dysfunction, lung transplantation / pulmonology, molecular biology: mRNA / mRNA expression, Medical and Health Sciences, Surgery, Clinical sciences
Abstract

Chronic lung allograft dysfunction (CLAD) remains the major complication limiting long-term survival among lung transplant recipients (LTRs). Limited understanding of CLAD immunopathogenesis and a paucity of biomarkers remain substantial barriers for earlier detection and therapeutic interventions for CLAD. We hypothesized the airway transcriptome would reflect key immunologic changes in disease. We compared airway brush-derived transcriptomic signatures in CLAD (n = 24) versus non-CLAD (n = 21) LTRs. A targeted assessment of the proteome using concomitant bronchoalveolar lavage (BAL) fluid for 24 cytokines/chemokines and alloimmune T cell responses was performed to validate the airway transcriptome. We observed an airway transcriptomic signature of differential genes expressed (DGEs) in CLAD marked by Type-1 immunity and striking upregulation of two endogenous immune regulators: indoleamine 2, 3 dioxygenase 1 (IDO-1) and tumor necrosis factor receptor superfamily 6B (TNFRSF6B). Advanced CLAD staging was associated with a more intense airway transcriptome signature. In a validation cohort using the identified signature, we found an area under the curve (AUC) of 0.77 for CLAD LTRs. Targeted proteomic analyses revealed a predominant Type-1 profile with detection of IFN-γ, TNF-α, and IL-1β as dominant CLAD cytokines, correlating with the airway transcriptome. The airway transcriptome provides novel insights into CLAD immunopathogenesis and biomarkers that may impact diagnosis of CLAD.

Published
2021

5. Advancing the pipeline of cystic fibrosis clinical trials: a new roadmap with a global trial network perspective

Author

Mayer-Hamblett, Nicole, Clancy, John Paul, Jain, Raksha, Donaldson, Scott H, Fajac, Isabelle, Goss, Christopher H, Polineni, Deepika, Ratjen, Felix, Quon, Bradley S, Zemanick, Edith T, Bell, Scott C, Davies, Jane C, Jain, Manu, Konstan, Michael W, Kerper, Natanya R, LaRosa, Tré, Mall, Marcus A, McKone, Edward, Pearson, Kelsie, Pilewski, Joseph M, Quittell, Lynne, Rayment, Jonathan H, Rowe, Steven M, Taylor-Cousar, Jennifer L, Retsch-Bogart, George, and Downey, Damian G

Published
2023
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12. Pseudomonas aeruginosa utilizes host polyunsaturated phosphatidylethanolamines to trigger theft-ferroptosis in bronchial epithelium

Author

Dar, Haider H, Tyurina, Yulia Y, Mikulska-Ruminska, Karolina, Shrivastava, Indira, Ting, Hsiu-Chi, Tyurin, Vladimir A, Krieger, James, St. Croix, Claudette M, Watkins, Simon, Bayir, Erkan, Mao, Gaowei, Ambruster, Catherine, Kapralov, Alexandr, Wang, Hong, Parsek, Matthew H, Anthonymuthu, Tamil S, Ogunsola, Abiola F, Flitter, Becca A, Freedman, Cody J, Gaston, Jordan R, Holman, Theodore R, Pilewski, Joseph M, Greenberger, Joel S, Mallampalli, Rama K, Doi, Yohei, Lee, Janet S, Bahar, Ivet, Bomberger, Jennifer M, Bayır, Hülya, and Kagan, Valerian E

Subjects
Microbiology, Medical Microbiology, Biomedical and Clinical Sciences, Biological Sciences, Lung, Orphan Drug, Rare Diseases, Cystic Fibrosis, Aetiology, 2.2 Factors relating to the physical environment, Infection, Congenital, Good Health and Well Being, Apoptosis, Cell Line, Epithelial Cells, Humans, Phosphatidylethanolamines, Pseudomonas Infections, Pseudomonas aeruginosa, Respiratory Mucosa, Respiratory Tract Infections, Bacterial infections, Cell Biology, Infectious disease, Medical and Health Sciences, Immunology, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Ferroptosis is a death program executed via selective oxidation of arachidonic acid-phosphatidylethanolamines (AA-PE) by 15-lipoxygenases. In mammalian cells and tissues, ferroptosis has been pathogenically associated with brain, kidney, and liver injury/diseases. We discovered that a prokaryotic bacterium, Pseudomonas aeruginosa, that does not contain AA-PE can express lipoxygenase (pLoxA), oxidize host AA-PE to 15-hydroperoxy-AA-PE (15-HOO-AA-PE), and trigger ferroptosis in human bronchial epithelial cells. Induction of ferroptosis by clinical P. aeruginosa isolates from patients with persistent lower respiratory tract infections was dependent on the level and enzymatic activity of pLoxA. Redox phospholipidomics revealed elevated levels of oxidized AA-PE in airway tissues from patients with cystic fibrosis (CF) but not with emphysema or CF without P. aeruginosa. We believe that the evolutionarily conserved mechanism of pLoxA-driven ferroptosis may represent a potential therapeutic target against P. aeruginosa-associated diseases such as CF and persistent lower respiratory tract infections.

Published
2018

13. Cystic fibrosis foundation consensus statements for the care of cystic fibrosis lung transplant recipients

Author

Shah, Pali, Lowery, Erin, Chaparro, Cecilia, Visner, Gary, Hempstead, Sarah E., Abraham, James, Bhakta, Zubin, Carroll, Maggie, Christon, Lillian, Danziger-Isakov, Lara, Diamond, Joshua M., Lease, Erika, Leonard, Jessica, Litvin, Marina, Poole, Ray, Vlahos, Fanny, Werchan, Chelsey, Murray, Michelle A., Tallarico, Erin, Faro, Albert, Pilewski, Joseph M., and Hachem, Ramsey R.

Published
2021
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14. Long-term safety and efficacy of tezacaftor–ivacaftor in individuals with cystic fibrosis aged 12 years or older who are homozygous or heterozygous for Phe508del CFTR (EXTEND): an open-label extension study

Author

Gibson, Ronald L., Jr., Rowe, Steven M., Lechtzin, Noah, Ahrens, Richard C., McCoy, Karen S., Aitken, Moira, Donaldson, Scott H., McBennett, Kimberly Ann, Pilewski, Joseph M., Billings, Joanne, Milla, Carlos, Rubenstein, Ronald, Rosenbluth, Daniel Brian, Linnemann, Rachel, Powers, Michael R., Fortner, Christopher, Frederick, Carla Anne, Liou, Theodore G., Black, Philip, Wang, Janice, Colombo, John L., Berdella, Maria, Indihar, Maria Veronica, Brown, Cynthia D., Anstead, Michael, Bilodeau, Lara, Sicilian, Leonard, Jain, Manu, Tolle, James Jerome, Moffett, Kathryn, Nasr, Samya, Taylor-Cousar, Jennifer, Barto, Tara Lynn, Antos, Nicholas, Rogers, John S., Quick, Bryon, Thompson, Henry R., Sawicki, Gregory, Barnett, Bruce, Zanni, Robert L., Smith, Thomas C., Schultz, Karen D., Keating, Claire, Flume, Patrick, Omlor, Gregory J., Ashare, Alix, Voter, Karen, Mehdi, Nighat, Ortiz, Maria Gabriela Tupayachi, Gardner, Tonia E., Boas, Steven R., Messore, Barbara, Zemanick, Edith, Jain, Raksha, McCarthy, Michael, Kissner, Dana G., Patel, Kapilkumar, McNamara, John, Philley, Julie, Berlinski, Ariel, Calimano, Francisco J., Chin, Terry, Conrad, Douglas, Daines, Cori, Raissy, Hengameh H., Keens, Thomas G., Lascano, Jorge E., McWilliams, Bennie, Morrissey, Brian, Reyes, Santiago, Chittivelu, Subramanyam, Hussain, Sabiha, Stone, Arvey, Wallace, James, Klingsberg, Ross, Biller, Julie A., Bui, Stephanie, Sommerburg, Olaf, Bignamini, Elisabetta, Collura, Mirella, Biner, Reta Fischer, Moller, Alexander, Salvatore, Donatello, Belleguic, Chantal, Bentur, Lea, Efrati, Ori, Kerem, Eitan, Prais, Dario, Gallego, Esther Quintana, Barry, Peter, Livnat-Levanon, Galit, Asensi, Jose Ramon Villa, Armstrong, David Stuart, de la Cruz, Oscar Asensio, Gilchrist, Francis, Tullis, Diana Elizabeth, Quon, Bradley, Lands, Larry C., Morrison, Nancy, Lavoie, Annick, Linnane, Barry, Elidemir, Okan, Ringshausen, Felix, Kappler, Matthias, Hebestreit, Helge, Mainz, Jochen, Kiefer, Alexander, Koerner-Rettberg, Cordula, Staab, Doris, Gleiber, Wolfgang, Pressler, Tacjana, Stehling, Florian, Hector, Andreas, Sutharsan, Sivagurunathan, Naehrlich, Lutz, Fischer, Rainald, Downey, Damian, Davies, Jane Carolyn, Ketchell, Robert Ian, Carroll, Mary Patricia, Doe, Simon, MacGregor, Gordon, Nash, Edward Fairbairn, Withers, Nicholas, Peckham, Daniel Gavin, Ledson, Martin James, Kansra, Sonal, Lee, Timothy William Rayner, Delaisi, Bertrand, Rault, Gilles, Le Bihan, Jean, Hubert, Dominique, Fajac, Isabelle, Sermet-Gaudelus, Isabelle, Bakker, Marleen, Arets, Bert, De Boeck, Christiane, Chiron, Raphael, Reix, Philippe, Mainguy, Catherine, van Braeckel, Eva, Malfroot, Anne, Durieu, Isabelle, Dufeu, Nadine Desmazes, Prevotat, Anne, van der Meer, Renske, Merkus, Petrus, Weersink, E.J.M., Gomez-Aguero, Isabel Barrio, Gartner, Silvia, Jover, Amparo Sole, Fernandez, Antonio Alvarez, Cox, Desmond William, McKone, Edward F., Plant, Barry James, Selvadurai, Hiranjan, Bowler, Simon David, Wainwright, Claire Elizabeth, Smith, Daniel, Middleton, Peter Gordon, Wilson, John William, Volpi, Sonia, Colombo, Carla, Fabrizzi, Benedetta, Lucidi, Vincenzina, Cresta, Federico, Cucchiara, Salvatore, Eber, Ernst, Ellemunter, Helmut, Huttegger, Isidor, Hjelte, Lena, Krantz, Christina, Gilljam, Marita, Flume, Patrick A, Downey, Damian G, Brown, Cynthia, De Boeck, Kris, Sawicki, Gregory S, Chang, Philip, Paz-Diaz, Hildegarde, Rubin, Jaime L, Yang, Yoojung, Hu, Xingdi, Pasta, David J, Millar, Stefanie J, Campbell, Daniel, Wang, Xin, Ahluwalia, Neil, Owen, Caroline A, and Wainwright, Claire E

Published
2021
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17. Incidence of Acute Cellular Rejection After Granulocyte Colony-Stimulating Factor in Lung Transplant Recipients.

Author

Fredrick, Stacy R., Iasella, Carlo J., Sacha, Lauren M., Rivosecchi, Ryan M., Morrell, Matthew R., Sanchez, Pablo G., Pilewski, Joseph M., Snyder, Mark E., McDyer, John F., and Moore, Cody A.

Subjects
PNEUMONIA, LUNG transplantation, PATIENTS, TRANSPLANTATION of organs, tissues, etc., SEX distribution, LOGISTIC regression analysis, RETROSPECTIVE studies, HOMOGRAFTS, DESCRIPTIVE statistics, MULTIVARIATE analysis, GRAFT rejection, LONGITUDINAL method, CHRONIC diseases, ODDS ratio, MEDICAL records, ACQUISITION of data, GRANULOCYTE-colony stimulating factor, CONFIDENCE intervals, NEUTROPENIA, TIME, IMMUNOSUPPRESSION
Abstract

Background: Neutropenia is a common complication in lung transplant recipients (LTRs). Filgrastim may be used to treat neutropenia in LTRs, but its consequences on acute cellular rejection (ACR) remain controversial. Objective: The purpose was to examine the association between filgrastim and incidence of ACR 6 months after filgrastim administration in LTRs. Secondary outcomes included burden of ACR, infections, chronic lung allograft dysfunction (CLAD), and survival. Methods: This was a matched cohort study of patients transplanted between January 2010 and October 2019. LTRs who received filgrastim for neutropenia were compared to a cohort who did not. LTRs were matched on transplant indication, sex, age, and time post-transplant and multivariable logistic regression models were used to evaluate the likelihood of ACR. Results: 212 patients were included in the analysis (106 in each group). 50 patients (47.2%) in the filgrastim group experienced ACR compared to 37 patients (34.9%) in the no filgrastim group (P =.070). In multivariable analysis, filgrastim use was not associated with ACR at 6 months (OR 1.409, 95% CI 0.772-2.571). Time to first ACR was shorter (P =.049) and 6-month ACR score was higher in the filgrastim group (.49 vs.33, P =.047). LTRs in the filgrastim group had higher incidence of bacterial pneumonia and 1-year mortality. Conclusions: Although not associated with increased likelihood of ACR at 6 months, our study found that filgrastim is associated with increased ACR burden and decreased time to ACR. This study can help inform clinicians of ACR risk after filgrastim use in LTRs. [ABSTRACT FROM AUTHOR]

Published
2024
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19. Cystic Fibrosis Foundation consensus guidelines for the care of individuals with advanced cystic fibrosis lung disease

Author

Kapnadak, Siddhartha G., Dimango, Emily, Hadjiliadis, Denis, Hempstead, Sarah E., Tallarico, Erin, Pilewski, Joseph M., Faro, Albert, Albright, James, Benden, Christian, Blair, Shaina, Dellon, Elisabeth P., Gochenour, Daniel, Michelson, Peter, Moshiree, Baharak, Neuringer, Isabel, Riedy, Carl, Schindler, Teresa, Singer, Lianne G., Young, Dave, Vignola, Lauren, Zukosky, Joan, and Simon, Richard H.

Published
2020
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27. First Successful Lung Transplantation for Sickle Cell Disease with Severe Pulmonary Arterial Hypertension and Pulmonary Veno‐Occlusive Disease

Author

George, M Patricia, Novelli, Enrico M, Shigemura, Norihisa, Simon, Marc A, Feingold, Brian, Krishnamurti, Lakshmanan, Morrell, Matthew R, Gries, Cynthia G, Haider, Syed, Johnson, Bruce A, Crespo, Maria M, Bhama, Jay K, Bermudez, Christian, Yousem, Samuel A, Toyoda, Yoshiya, Champion, Hunter C, Pilewski, Joseph M, and Gladwin, Mark T

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Clinical Sciences, Hematology, Sickle Cell Disease, Lung, Transplantation, Orphan Drug, Rare Diseases, Organ Transplantation, Respiratory, Cardiovascular, lung transplantation, sickle cell disease, pulmonary arterial hypertension, pulmonary veno-occlusive disease, Cardiorespiratory Medicine and Haematology, Cardiovascular medicine and haematology
Abstract

Little is known about the use of lung transplantation in the management of sickle cell disease-associated pulmonary arterial hypertension (SCD-PAH). We present clinical and pathological data and report the first successful outcome of bilateral lung transplantation in a patient with severe SCD-PAH and pulmonary veno-occlusive disease (PVOD). We discuss the complexities of multidisciplinary planning and management of lung transplantation in patients with SCD-associated pulmonary vascular complications. This case reports the first documented successful lung transplant and first case of PVOD in a patient with SCD-PAH.

Published
2013

30. Gastrin-releasing peptide receptor expression in non-cancerous bronchial epithelia is associated with lung cancer: a case-control study.

Author

Egloff, Ann Marie, Gaither Davis, Autumn, Shuai, Yongli, Land, Stephanie, Pilewski, Joseph M, Luketich, James D, Landreneau, Rodney, Miller, York E, Grandis, Jennifer R, and Siegfried, Jill M

Subjects
Lung, Bronchi, Humans, Adenocarcinoma, Carcinoma, Non-Small-Cell Lung, Carcinoma, Squamous Cell, Lung Neoplasms, Receptors, Bombesin, Risk, Case-Control Studies, Smoking, Adult, Aged, Aged, 80 and over, Middle Aged, Female, Male, Small Cell Lung Carcinoma, Adenocarcinoma of Lung, Gastrin-releasing peptide receptor, lung cancer risk, case-control study, surrogate tissue, Carcinoma, Non-Small-Cell Lung, Squamous Cell, Receptors, Bombesin, and over, Respiratory System, Cardiorespiratory Medicine and Haematology, Clinical Sciences
Abstract

BackgroundNormal bronchial tissue expression of GRPR, which encodes the gastrin-releasing peptide receptor, has been previously reported by us to be associated with lung cancer risk in 78 subjects, especially in females. We sought to define the contribution of GRPR expression in bronchial epithelia to lung cancer risk in a larger case-control study where adjustments could be made for tobacco exposure and sex.MethodsWe evaluated GRPR mRNA levels in histologically normal bronchial epithelial cells from 224 lung cancer patients and 107 surgical cancer-free controls. Associations with lung cancer were tested using logistic regression models.ResultsBronchial GRPR expression was significantly associated with lung cancer (OR = 4.76; 95% CI = 2.32-9.77) in a multivariable logistic regression (MLR) model adjusted for age, sex, smoking status and pulmonary function. MLR analysis stratified by smoking status indicated that ORs were higher in never and former smokers (OR = 7.74; 95% CI = 2.96-20.25) compared to active smokers (OR = 1.69; 95% CI = 0.46-6.33). GRPR expression did not differ by subject sex, and lung cancer risk associated with GRPR expression was not modified by sex.ConclusionsGRPR expression in non-cancerous bronchial epithelium was significantly associated with the presence of lung cancer in never and former smokers. The association in never and former smokers was found in males and females. Association with lung cancer did not differ by sex in any smoking group.

Published
2012

35. Role of Extracellular Vesicles in the Propagation of Lung Fibrosis in Systemic Sclerosis.

Author

Mouawad, Joe E., Sanderson, Matthew, Sharma, Shailza, Helke, Kristi L., Pilewski, Joseph M., Nadig, Satish N., and Feghali‐Bostwick, Carol

Subjects
PULMONARY fibrosis treatment, IN vitro studies, TRANSFORMING growth factors-beta, REVERSE transcriptase polymerase chain reaction, RODENTS, IN vivo studies, ACADEMIC medical centers, LUNG transplantation, SYSTEMIC scleroderma, CELL communication, ELECTRON microscopy, IMMUNOBLOTTING, EXTRACELLULAR vesicles, NANOPARTICLES, DISEASE complications
Abstract

Objectives: Systemic sclerosis (SSc) has the highest mortality rate among the rheumatic diseases, with lung fibrosis leading as the cause of death. A characteristic of severe SSc‐related lung fibrosis is its progressive nature. Although most research has focused on the pathology of the fibrosis, the mechanism mediating the fibrotic spread remains unclear. We hypothesized that extracellular vesicle (EV) communication drives the propagation of SSc lung fibrosis. Methods: EVs were isolated from normal (NL) or SSc‐derived human lungs and primary lung fibroblasts (pLFs). EVs were also isolated from human fibrotic lungs and pLFs induced experimentally with transforming growth factor‐β (TGFβ). Fibrotic potency of EVs was assessed using functional assays in vitro and in vivo. Transmission electron microscopy, nanoparticle tracking analysis, real‐time quantitative polymerase chain reaction (RT‐qPCR), immunoblotting, and immunofluorescence were used to analyze EVs, their cargo, extracellular matrix (ECM) fractions, and conditioned media. Results: SSc lungs and pLFs released significantly more EVs than NL lungs, and their EVs showed increased fibrotic content and activity. TGFβ‐stimulated NL lung cores and pLFs increased packaging of fibrotic proteins, including fibronectin, collagens, and TGFβ, into released EVs. The EVs induced a fibrotic phenotype in recipient pLFs and in vivo in mouse lungs. Furthermore, EVs interacted with and contributed to the ECM. Finally, suppressing EV release in vivo reduced severity of murine lung fibrosis. Conclusions: Our findings highlight EV communication as a novel mechanism for propagation of SSc lung fibrosis. Identifying therapies that reduce EV release, activity, and/or fibrotic cargo in SSc patient lungs may be a viable therapeutic strategy to improve fibrosis. [ABSTRACT FROM AUTHOR]

Published
2023
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47. Phage therapy in a lung transplant recipient with cystic fibrosis infected with multidrug‐resistant Burkholderia multivorans.

Author

Haidar, Ghady, Chan, Benjamin K., Cho, Shu‐Ting, Hughes Kramer, Kailey, Nordstrom, Hayley R., Wallace, Nathan R., Stellfox, Madison E., Holland, Mische, Kline, Ellen G., Kozar, Jennifer M., Kilaru, Silpa D., Pilewski, Joseph M., LiPuma, John J., Cooper, Vaughn S., Shields, Ryan K., and Van Tyne, Daria

Subjects
LUNG transplantation, CYSTIC fibrosis, BACTERIOPHAGES, BURKHOLDERIA infections, WHOLE genome sequencing
Abstract

Background: There is increased interest in bacteriophage (phage) therapy to treat infections caused by antibiotic‐resistant bacteria. A lung transplant recipient with cystic fibrosis and Burkholderia multivorans infection was treated with inhaled phage therapy for 7 days before she died. Methods: Phages were given via nebulization through the mechanical ventilation circuit. Remnant respiratory specimens and serum were collected. We quantified phage and bacterial deoxyribonucleic acid (DNA) using quantitative polymerase chain reaction, and tested phage neutralization in the presence of patient serum. We performed whole genome sequencing and antibiotic and phage susceptibility testing on 15 B. multivorans isolates. Finally, we extracted lipopolysaccharide (LPS) from two isolates and visualized their LPS using gel electrophoresis. Results: Phage therapy was temporally followed by a temporary improvement in leukocytosis and hemodynamics, followed by worsening leukocytosis on day 5, deterioration on day 7, and death on day 8. We detected phage DNA in respiratory samples after 6 days of nebulized phage therapy. Bacterial DNA in respiratory samples decreased over time, and no serum neutralization was detected. Isolates collected between 2001 and 2020 were closely related but differed in their antibiotic and phage susceptibility profiles. Early isolates were not susceptible to the phage used for therapy, while later isolates, including two isolates collected during phage therapy, were susceptible. Susceptibility to the phage used for therapy was correlated with differences in O‐antigen profiles of an early versus a late isolate. Conclusions: This case of clinical failure of nebulized phage therapy highlights the limitations, unknowns, and challenges of phage therapy for resistant infections. [ABSTRACT FROM AUTHOR]

Published
2023
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48. Embedded Specialist Palliative Care in Cystic Fibrosis: Results of a Randomized Feasibility Clinical Trial.

Author

Kavalieratos, Dio, Lowers, Jane, Moreines, Laura T., Hoydich, Zachariah P., Arnold, Robert M., Yabes, Jonathan G., Richless, Connie, Ikejiani, Dara Z., Teuteberg, Winifred, and Pilewski, Joseph M.

Subjects
CYSTIC fibrosis treatment, PILOT projects, CLINICS, RANDOMIZED controlled trials, RESEARCH funding, QUALITY of life, OXYGEN therapy, STATISTICAL sampling, PALLIATIVE treatment
Abstract

Background: Cystic fibrosis (CF) is a progressive genetic disease characterized by multisystem symptom burden. Specialist palliative care (PC), as a model of care, has been shown to be effective in improving quality of life and reducing symptom burden in other conditions, but has not been tested in CF. Objectives: To develop and test the feasibility and acceptability of a specialist PC intervention embedded within an outpatient CF clinic. Design: Single-site, equal-allocation randomized pilot study comparing usual care with addition of four protocolized quarterly visits with a PC nurse practitioner. Participants: Adults with CF age ≥18 years with any of the following: FEV1% predicted ≤50, ≥2 CF-related hospitalizations in the past 12 months, supplemental oxygen use, or noninvasive mechanical ventilation use, and moderate-or-greater severity of any symptoms on the Edmonton Symptom Assessment Scale. Measurements: Randomization rate, intervention visit completion, data completements, participant ratings of intervention acceptability and benefit, and intervention delivery fidelity. Results: We randomized 50 adults with CF of 65 approached (77% randomization rate) to intervention (n = 25) or usual care (n = 25), mean age 38, baseline mean FEV1% predicted 41.8 (usual care), and 41.2 (intervention). No participants withdrew, five were lost to follow-up, and two died (88% retention). In the intervention group, 23 of 25 completed all study visits; 94% stated the intervention was not burdensome, and 97.6% would recommend the intervention to others with CF. More than 90% of study visits addressed topics prescribed by intervention manual. Conclusions: Adding specialist PC to standard clinic visits for adults with CF is feasible and acceptable. [ABSTRACT FROM AUTHOR]

Published
2023
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49. Reduced Cathepsin L expression and secretion into the extracellular milieu contribute to lung fibrosis in systemic sclerosis.

Author

Mouawad, Joe E, Sharma, Shailza, Renaud, Ludivine, Pilewski, Joseph M, Nadig, Satish N, and Feghali-Bostwick, Carol

Subjects
TISSUE analysis, TRANSFORMING growth factors-beta, IN vitro studies, FIBROBLASTS, IN vivo studies, LUNGS, SYSTEMIC scleroderma, PROTEOLYTIC enzymes, METABOLISM, GENE expression, MOLECULAR biology, IMMUNOBLOTTING, ENZYME-linked immunosorbent assay, FLUORESCENT antibody technique, PULMONARY fibrosis, POLYMERASE chain reaction, EXTRACELLULAR vesicles, RECOMBINANT proteins, PEPTIDES, DISEASE risk factors, DISEASE complications
Abstract

Objectives Lung fibrosis is the leading cause of death in SSc, with no cure currently available. Antifibrotic Endostatin (ES) production does not reach therapeutic levels in SSc patients, suggesting a deficit in its release from Collagen XVIII by the main cleavage enzyme, Cathepsin L (CTSL). Thus, elucidating a potential deficit in CTSL expression and activity unravels an underlying molecular cause for SSc-driven lung fibrosis. Methods Fibrosis was induced experimentally using TGF-β in vitro , in primary human lung fibroblasts (pLFs), and ex vivo , in human lung tissues. ES and CTSL expression was quantified using ELISA, RT-qPCR, immunoblotting or immunofluorescence. Recombinant NC1-FLAG peptide was used to assess CTSL cleavage activity. CTSL expression was also compared between SSc vs normal (NL)-derived pLFs and lung tissues. Results ES levels were significantly reduced in media conditioned by TGF-β-induced pLFs. TGF-β-stimulated pLFs significantly reduced expression and secretion of CTSL into the extracellular matrix (ECM). CTSL was also sequestered in its inactive form into extracellular vesicles, further reducing its availability in the ECM. Media conditioned by TGF-β-induced pLFs showed reduced cleavage of NC1-Flag and reduced release of the antifibrotic ES fragment. SSc-derived pLFs and lung tissues expressed significantly lower levels of CTSL compared with NL. Conclusions Our findings identify CTSL as a protein protective against lung fibrosis via its activation of antifibrotic ES, and whose expression in SSc pLFs and lung tissues is suppressed. Identifying strategies to boost CTSL endogenous levels in SSc patients could serve as a viable therapeutic strategy. [ABSTRACT FROM AUTHOR]

Published
2023
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