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4. Hypoxia Abrogates Tumor-Suppressive Activities of C/EBPδ in Pancreatic Cancer.

Author

Hartl, Leonie, ten Brink, Marieke S., Aberson, Hella L., Koster, Jan, Zwijnenburg, Danny A., Duitman, JanWillem, Bijlsma, Maarten F., and Spek, C. Arnold

Subjects
TRANSCRIPTION factors, PANCREATIC duct, PANCREATIC cancer, RNA sequencing, SURVIVAL rate
Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a dismal disease with a low 5-year survival rate of only 13%. Despite intense research efforts, PDAC remains insufficiently understood. In part, this is attributed to opposing effects of key players being unraveled, including the stroma but also molecules that act in a context-dependent manner. One such molecule is the transcription factor C/EBPδ, where we recently showed that C/EBPδ exerts tumor-suppressive effects in PDAC cells in vitro. To better understand the role of C/EBPδ in different contexts and the development of PDAC, we here build on these findings and assess the effect of C/EBPδ in a PDAC model in mice. We establish that the lack of oxygen in vivo—hypoxia—counteracts the tumor-suppressive effects of C/EBPδ, and identify a reciprocal feedback loop between C/EBPδ and HIF-1α. RNA sequencing of C/EBPδ-induced cells under hypoxia also suggests that the growth-limiting effects of C/EBPδ decrease with oxygen tension. Consequently, in vitro proliferation assays reveal that the tumor-suppressive activities of C/EBPδ are abrogated due to hypoxia. This study demonstrates the importance of considering major physiological parameters in preclinical approaches. [ABSTRACT FROM AUTHOR]

Published
2024
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5. The alveolar fibroproliferative response in moderate to severe COVID-19-related acute respiratory distress syndrome and one-year follow up

Author

Zhang, Shiqi, primary, Boers, Leonoor S., additional, de Brabander, Justin, additional, van den Heuvel, Laura B., additional, Blok, Siebe G., additional, Kullberg, Robert F.J., additional, Smids-Dierdorp, Barbara S., additional, Dekker, Tamara, additional, Aberson, Hella L., additional, Meijboom, Lilian J., additional, Vlaar, Alexander P.J., additional, Heunks, Leo, additional, Nossent, Esther J., additional, van der Poll, Tom, additional, Bos, Lieuwe D.J., additional, and Duitman, JanWillem, additional

Published
2023
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7. The alveolar fibroproliferative response in moderate to severe COVID-19-related acute respiratory distress syndrome and 1-yr follow-up.

Author

Shiqi Zhang, Boers, Leonoor S., de Brabander, Justin, van den Heuvel, Laura B., Blok, Siebe G., Kullberg, Robert F. J., Smids-Dierdorp, Barbara S., Dekker, Tamara, Aberson, Hella L., Meijboom, Lilian J., Vlaar, Alexander P. J., Heunks, Leo, Nossent, Esther J., van der Poll, Tom, Bos, Lieuwe D. J., and Duitman, JanWillem

Subjects
ADULT respiratory distress syndrome, LUNGS, COVID-19 pandemic, PULMONARY fibrosis, VITAL capacity (Respiration), COVID-19
Abstract

COVID-19-related acute respiratory distress syndrome (ARDS) can lead to long-term pulmonary fibrotic lesions. Alveolar fibroproliferative response (FPR) is a key factor in the development of pulmonary fibrosis. N-terminal peptide of procollagen III (NT-PCP-III) is a validated biomarker for activated FPR in ARDS. This study aimed to assess the association between dynamic changes in alveolar FPR and long-term outcomes, as well as mortality in COVID-19 ARDS patients. We conducted a prospective cohort study of 154 COVID-19 ARDS patients. We collected bronchoalveolar lavage (BAL) and blood samples for measurement of 17 pulmonary fibrosis biomarkers, including NT-PCP-III. We assessed pulmonary function and chest computed tomography (CT) at 3 and 12 mo after hospital discharge. We performed joint modeling to assess the association between longitudinal changes in biomarker levels and mortality at day 90 after starting mechanical ventilation. 154 patients with 284 BAL samples were analyzed. Of all patients, 40% survived to day 90, of whom 54 completed the follow-up procedure. A longitudinal increase in NT-PCP-III was associated with increased mortality (HR 2.89, 95% CI: 2.55–3.28; P < 0.001). Forced vital capacity and diffusion for carbon monoxide were impaired at 3 mo but improved significantly at one year after hospital discharge (P = 0.03 and P = 0.004, respectively). There was no strong evidence linking alveolar FPR during hospitalization and signs of pulmonary fibrosis in pulmonary function or chest CT images during 1-yr follow-up. In COVID-19 ARDS patients, alveolar FPR during hospitalization was associated with higher mortality but not with the presence of long-term fibrotic lung sequelae within survivors. NEW & NOTEWORTHY This is the first prospective study on the longitudinal alveolar fibroproliferative response in COVID-19 ARDS and its relationship with mortality and long-term follow-up. We used the largest cohort of COVID-19 ARDS patients who had consecutive bronchoalveolar lavages and measured 17 pulmonary fibroproliferative biomarkers. We found that a higher fibroproliferative response during admission was associated with increased mortality, but not correlated with long-term fibrotic lung sequelae in survivors. [ABSTRACT FROM AUTHOR]

Published
2024
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8. Absence of COVID-19 associated mucormycosis in a tertiary intensive care unit in the Netherlands.

Author

Schippers, J. R., Verweij, P. E., Heunks, L. M. A., van Dijk, K., the ArtDECO consortium, Nossent, Esther J., Duitman, JanWillem, Saris, Anno, De Vries, Heder, Meijboom, Lilian J., Bos, Lieuwe D. J., Blok, Siebe G., Schuurman, Alex R., Reijnders, Tom D. Y., Vallejo, Juan J. Garcia, Bontkes, Hetty, Vlaar, Alexander P. J., Wiersinga, W. Joost, Lutter, René, and van der Poll, Tom

Subjects
INTENSIVE care units, MUCORMYCOSIS, TERTIARY care, COVID-19, CRITICALLY ill, DIAGNOSTIC use of polymerase chain reaction
Abstract

Mucormycosis is a severe complication in critically ill COVID-19 patients. Throughout the pandemic, a notable prevalence of mucormycosis has been observed in the Indian population, whereas lower occurrences have been reported in Europe. However, limited data exist regarding its prevalence in Europe, which is potentially underestimated due to the low sensitivity of bronchoalveolar lavage (BAL) cultures. We aimed to evaluate the prevalence of mucormycosis in a high-risk critically ill COVID-19 population in the Netherlands, and to evaluate the potential benefit of adding Mucor PCR to BAL as part of routine follow-up. In this study, we included 1035 critically ill COVID-19 patients admitted to either one of the two ICUs at AmsterdamUMC between March 2020 and May 2022; of these, 374 had undergone at least one bronchoscopy. Following the AmsterdamUMC protocols, bronchoscopies were conducted weekly until clinical improvement was achieved. We cultured BAL fluid for fungi and used PCR and galactomannan testing to detect Aspergillus spp. Additionally, we retrospectively performed qPCR targeting Mucorales DNA in the BAL of 89 deceased patients. All cultures were negative for Mucorales, whereas 42 (11%) cultures were positive for Aspergillus. Furthermore, qPCR targeting Mucorales was negative in all 89 deceased patients. This study showed that pulmonary mucormycosis was not present in critically ill COVID-19 patients in two tertiary care ICUs. These results indicate routine Mucorales qPCR screening is not clinically necessary in a high-standard-of-care tertiary ICU in a low-endemic area. [ABSTRACT FROM AUTHOR]

Published
2023
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10. Persistent alveolar inflammatory response in critically ill patients with COVID-19 is associated with mortality.

Author

de Brabander, Justin, Boers, Leonoor S., Kullberg, Robert F. J., Shiqi Zhang, Nossent, Esther J., Heunks, Leo M. A., Vlaar, Alexander P. J., Bonta, Peter I., Schultz, Marcus J., van der Poll, Tom, Duitman, JanWillem, and Bos, Lieuwe D. J.

Subjects
COVID-19, PULMONARY alveolar proteinosis, FIBROBLAST growth factor 2, GRANULOCYTE-colony stimulating factor, CRITICALLY ill, INFLAMMATION, PULMONARY embolism
Published
2023
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13. Lung Microbiota of Critically Ill Patients with COVID-19 Are Associated with Nonresolving Acute Respiratory Distress Syndrome

Author

Kullberg, Robert F. J., primary, de Brabander, Justin, additional, Boers, Leonoor S., additional, Biemond, Jason J., additional, Nossent, Esther J., additional, Heunks, Leo M. A., additional, Vlaar, Alexander P. J., additional, Bonta, Peter I., additional, van der Poll, Tom, additional, Duitman, JanWillem, additional, Bos, Lieuwe D. J., additional, Wiersinga, W. Joost, additional, Saris, Anno, additional, De Vries, Heder, additional, Meijboom, Lilian J., additional, Blok, Siebe G., additional, Schuurman, Alex R., additional, Reijnders, Tom D.Y., additional, Garcia Vallejo, Juan J., additional, Bontkes, Hetty, additional, Lutter, René, additional, Bogaard, Harm Jan, additional, de Bruin, S., additional, Koning, R., additional, van Agtmael, M.A., additional, Algera, A.G., additional, van Baarle, F.E.H.P., additional, Bax, D.J.C., additional, Beudel, M., additional, Bomers, M., additional, Botta, M., additional, de Bree, G.J., additional, Bugiani, M., additional, Bulle, E.B., additional, Chouchane, O., additional, Cloherty, A.P.M., additional, Elbers, P.E., additional, Fleuren, L.M., additional, Geerlings, S.E., additional, Geerts, B.F., additional, Geijtenbeek, T.B.H., additional, Girbes, A.R.J., additional, Goorhuis, A., additional, Grobusch, M.P., additional, Hafkamp, F.M.J., additional, Hagens, L.A., additional, Hamann, J., additional, Harris, V.C., additional, Hemke, R., additional, Hermans, S.M., additional, Hollmann, M.W., additional, Horn, J., additional, Hovius, J.W., additional, de Jong, M.D., additional, van Mourik, N., additional, Nellen, J.F, additional, Paulus, F., additional, Peters, E., additional, Preckel, B., additional, Raasveld, S.J., additional, Schinkel, M., additional, Schultz, M.J., additional, Sigaloff, K., additional, Smit, M.R., additional, Stijnis, C., additional, Stilma, W., additional, Teunissen, C.E., additional, Thoral, P., additional, Tsonas, A.M., additional, van der Valk, M., additional, Veelo, D.P., additional, van Vugt, M., additional, Wouters, D., additional, Zwinderman, A.H., additional, Brouwer, M.C., additional, and van de Beek, D., additional

Published
2022
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26. Pulmonary Procoagulant and Innate Immune Responses in Critically Ill COVID-19 Patients

Author

Nossent, Esther J., primary, Schuurman, Alex R., additional, Reijnders, Tom D.Y., additional, Saris, Anno, additional, Jongerius, Ilse, additional, Blok, Siebe G., additional, de Vries, Heder, additional, Duitman, JanWillem, additional, Vonk Noordegraaf, Anton, additional, Meijboom, Lilian J., additional, Lutter, René, additional, Heunks, Leo, additional, Bogaard, Harm Jan, additional, and van der Poll, Tom, additional

Published
2021
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28. Distinct cellular immune profiles in the airways and blood of critically ill patients with COVID-19

Author

Saris, Anno, primary, Reijnders, Tom D Y, additional, Nossent, Esther J, additional, Schuurman, Alex R, additional, Verhoeff, Jan, additional, Asten, Saskia van, additional, Bontkes, Hetty, additional, Blok, Siebe, additional, Duitman, Janwillem, additional, Bogaard, Harm-Jan, additional, Heunks, Leo, additional, Lutter, Rene, additional, van der Poll, Tom, additional, and Garcia Vallejo, Juan J, additional

Published
2021
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29. CCAAT/Enhancer-Binding Protein Delta (C/EBPδ): A Previously Unrecognized Tumor Suppressor that Limits the Oncogenic Potential of Pancreatic Ductal Adenocarcinoma Cells

Author

Hartl, Leonie, primary, Duitman, JanWillem, additional, Aberson, Hella L., additional, Chen, Kan, additional, Dijk, Frederike, additional, Roelofs, Joris J.T.H., additional, Dings, Mark P.G., additional, Hooijer, Gerrit K.J., additional, Hernanda, Pratika Y., additional, Pan, Qiunwei, additional, Busch, Olivier R., additional, Besselink, Marc G.H., additional, Boerman, Ton, additional, Peppelenbosch, Maikel P., additional, Bijlsma, Maarten F., additional, and Spek, C. Arnold, additional

Published
2020
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32. CCAAT/enhancer binding protein delta (C/EBPδ) deficiency does not affect bleomycin-induced pulmonary fibrosis

Author

Duitman, JanWillem, Cong, Lin, Sophie, Moog, Madeleine, Jaillet, Yves, Castier, Aurélie, Cazes, Keren S, Borensztajn, Bruno, Crestani, and C Arnold, Spek

Subjects
IPF, Special Issue Article, C/EBPδ, transcription factor, Pulmonary fibrosis
Abstract

Background Idiopathic pulmonary fibrosis is a devastating fibrotic diffuse parenchymal lung disorder that remains refractory to pharmacological therapies. Therefore, novel treatments are urgently required. CCAAT/enhancer binding protein delta (C/EBPδ) is a transcription factor that mediates critical cellular functions in pathophysiology and which was recently suggested to be a key regulatory component in IPF. The purpose of this study was to prove or refute the importance of C/EBPδ in pulmonary fibrosis. Methods Pulmonary fibrosis was induced by intranasal instillation of bleomycin into wild-type and C/EBPδ deficient mice. At different time intervals after bleomycin instillation, fibrosis was assessed by hydroxyproline analysis, histochemistry and q-PCR for fibrotic marker expression. Results C/EBPδ deficient mice developed pulmonary fibrosis to a similar degree as wildtype mice as evident from similar Ashcroft scores, hydroxyproline levels and expression levels of collagen, fibronectin and α-smooth muscle actin at both 14 and 21 days after bleomycin instillation. The resolution of fibrosis, assessed at 48 days after bleomycin instillation, was also similar in wildtype and C/EBPδ deficient mice. In line with the lack of effect of C/EBPδ on fibrosis progression/resolution, macrophage recruitment and/or differentiation were also not different in wildtype or C/EBPδ deficient mice. Conclusions Overall, C/EBPδ does not seem to affect bleomycin-induced experimental pulmonary fibrosis and we challenge the importance of C/EBPδ in pulmonary fibrosis. Relevance for patients This study shows that the transcription factor C/EBPδ does not play a major role in the development of pulmonary fibrosis. Pharmacological targeting of C/EBPδ is therefore not likely to have a beneficial effect for patients suffering from pulmonary fibrosis.

Published
2019

33. Enrichment of CCR6+CD8+ T cells and CCL20 in the lungs of mechanically ventilated patients with COVID‐19.

Author

Saris, Anno, Reijnders, Tom D.Y., Reijm, Martine, Hollander, Jolien C., de Buck, Kim, Schuurman, Alex R., Duitman, JanWillem, Heunks, Leo, Aman, Jurjan, Bogaard, Harm Jan, Nossent, Esther J., van der Poll, Tom, and Bontkes, Hetty J.

Subjects
COVID-19, T cells, GRANZYMES, LUNGS, T helper cells, T cell receptors
Abstract

Enrichment of CCR6+CD8+ T cells and CCL20 in the lungs of mechanically ventilated patients with COVID-19 We hypothesized that T cells from patients hospitalized with severe COVID-19, particularly those admitted to the intensive care unit (ICU), have a disturbed expression pattern of chemokine receptors that hampers the migration of relevant effector T cells from the blood to the lungs. Data were collected from consecutive enrolled patients with 1-4 patients per experiment. gl When compared with ward patients, CCR4 expression was higher on circulating T cells from ICU patients. [Extracted from the article]

Published
2021
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34. CCAAT/enhancer binding protein delta (C/EBPδ) deficiency does not affect bleomycin-induced pulmonary fibrosis

Author

Duitman JanWillem, Cong Lin, Yves Castier, Keren S. Borensztajn, Sophie Moog, Bruno Crestani, Aurélie Cazes, C. Arnold Spek, and Madeleine Jaillet

Subjects
business.industry, medicine.disease, Bleomycin, Pathophysiology, chemistry.chemical_compound, Idiopathic pulmonary fibrosis, Hydroxyproline, chemistry, Fibrosis, Enhancer binding, Pulmonary fibrosis, Cancer research, Medicine, business, Transcription factor
Abstract

Background Idiopathic pulmonary fibrosis is a devastating fibrotic diffuse parenchymal lung disorder that remains refractory to pharmacological therapies. Therefore, novel treatments are urgently required. CCAAT/enhancer binding protein delta (C/EBPδ) is a transcription factor that mediates critical cellular functions in pathophysiology and which was recently suggested to be a key regulatory component in IPF. The purpose of this study was to prove or refute the importance of C/EBPδ in pulmonary fibrosis. Methods Pulmonary fibrosis was induced by intranasal instillation of bleomycin into wild-type and C/EBPδ deficient mice. At different time intervals after bleomycin instillation, fibrosis was assessed by hydroxyproline analysis, histochemistry and q-PCR for fibrotic marker expression. Results C/EBPδ deficient mice developed pulmonary fibrosis to a similar degree as wildtype mice as evident from similar Ashcroft scores, hydroxyproline levels and expression levels of collagen, fibronectin and α-smooth muscle actin at both 14 and 21 days after bleomycin instillation. The resolution of fibrosis, assessed at 48 days after bleomycin instillation, was also similar in wildtype and C/EBPδ deficient mice. In line with the lack of effect of C/EBPδ on fibrosis progression/resolution, macrophage recruitment and/or differentiation were also not different in wildtype or C/EBPδ deficient mice. Conclusions Overall, C/EBPδ does not seem to affect bleomycin-induced experimental pulmonary fibrosis and we challenge the importance of C/EBPδ in pulmonary fibrosis. Relevance for patients This study shows that the transcription factor C/EBPδ does not play a major role in the development of pulmonary fibrosis. Pharmacological targeting of C/EBPδ is therefore not likely to have a beneficial effect for patients suffering from pulmonary fibrosis.

Published
2018

42. Human airway trypsin‐like protease exerts potent, antifibrotic action in pulmonary fibrosis

Author

Menou, Awen, primary, Flajolet, Pauline, additional, Duitman, JanWillem, additional, Justet, Aurélien, additional, Moog, Sophie, additional, Jaillet, Madeleine, additional, Tabèze, Laure, additional, Solhonne, Brigitte, additional, Garnier, Marc, additional, Mal, Hervé, additional, Mordant, Pierre, additional, Castier, Yves, additional, Cazes, Aurélie, additional, Sallenave, Jean‐Michel, additional, A. Mailleux, Arnaud, additional, and Crestani, Bruno, additional

Published
2018
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43. Human Airway Trypsin-like protease exerts potent anti-fibrotic role in vivo

Author

Menou, Awen, primary, Moog, Sophie, additional, Flajolet, Pauline, additional, Duitman, JanWillem, additional, Justet, Aurélien, additional, Solhonne, Brigitte, additional, Castier, Yves, additional, Mordant, Pierre, additional, Mal, Hervé, additional, Cazes, Aurélie, additional, Sallenave, Jean-Michel, additional, Mailleux, Arnaud, additional, and Crestani, Bruno, additional

Published
2017
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46. Sepsis Patients Display a Reduced Capacity to Activate Nuclear Factor-κB in Multiple Cell Types*

Author

Hoogendijk, Arie J., primary, Garcia-Laorden, M. Isabel, additional, van Vught, Lonneke A., additional, Wiewel, Maryse A., additional, Belkasim-Bohoudi, Hakima, additional, Duitman, JanWillem, additional, Horn, Janneke, additional, Schultz, Marcus J., additional, Scicluna, Brendon P., additional, van ‘t Veer, Cornelis, additional, de Vos, Alex F., additional, and van der Poll, Tom, additional

Published
2017
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48. Protease‐activated receptor‐1 contributes to renal injury and interstitial fibrosis during chronic obstructive nephropathy.

Author

Waasdorp, Maaike, de Rooij, Dennis M., Florquin, Sandrine, Duitman, JanWillem, and Spek, C. Arnold

Subjects
RENAL fibrosis, FIBROBLASTS, PROTEASE-activated receptors, KIDNEY diseases, MESENCHYMAL stem cells
Abstract

End‐stage renal disease, the final stage of all chronic kidney disorders, is associated with renal fibrosis and inevitably leads to renal failure and death. Transition of tubular epithelial cells (TECs) into mesenchymal fibroblasts constitutes a proposed mechanism underlying the progression of renal fibrosis and here we assessed whether protease‐activated receptor (PAR)‐1, which recently emerged as an inducer of epithelial‐to‐mesenchymal transition (EMT), aggravates renal fibrosis. We show that PAR‐1 activation on TECs reduces the expression of epithelial markers and simultaneously induces mesenchymal marker expression reminiscent of EMT. We next show that kidney damage was reduced in PAR‐1‐deficient mice during unilateral ureter obstruction (UUO) and that PAR‐1‐deficient mice develop a diminished fibrotic response. Importantly, however, we did hardly observe any signs of mesenchymal transition in both wild‐type and PAR‐1‐deficient mice suggesting that diminished fibrosis in PAR‐1‐deficient mice is not due to reduced EMT. Instead, the accumulation of macrophages and fibroblasts was significantly reduced in PAR‐1‐deficient animals which were accompanied by diminished production of MCP‐1 and TGF‐β. Overall, we thus show that PAR‐1 drives EMT of TECs in vitro and aggravates UUO‐induced renal fibrosis although this is likely due to PAR‐1‐dependent pro‐fibrotic cytokine production rather than EMT. [ABSTRACT FROM AUTHOR]

Published
2019
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