Mesothelial cells activate the plasma kallikrein-kinin system during pleural inflammation

Our plain-English summary of Mesothelial cells activate the plasma kallikrein-kinin system during pleural inflammation, by J.F. Varano Della Vergiliana, S. Lansley, A.L. Tan, et al (Biological Chemistry, 2011).

The study

• Authors: J.F. Varano Della Vergiliana, S. Lansley, A.L. Tan, J. Creaney, Y.C. Lee, G.A. Stewart
• Journal: Biological Chemistry
• Published: 2011;392(7):633-42
• Cited by: 5 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Abstract Pleural inflammation underlies the formation of most exudative pleural effusions and the plasma kallikrein-kinin system (KKS) is known to contribute. Mesothelial cells are the predominant cell type in the pleural cavity, but their potential role in plasma KKS activation and BK production has not been studied. Bradykinin concentrations were higher in pleural fluids than the corresponding serum samples in patients with a variety of diseases. Bradykinin concentrations did not correlate with disease diagnosis, but were elevated in exudative effusions. It was demonstrated, using a range of primary and transformed mesothelial and mesothelioma cell lines, that cells assembled high molecular weight kininogen and plasma prekallikrein to liberate bradykinin, a process inhibited by novobiocin, a heat shock protein 90 (HSP90) inhibitor, cysteine, bradykinin and protamine sulphate. Of the common plasma prekallikrein activators, mesothelial cells expressed HSP90, but not prolylcarboxypeptidase or Factor XII. Calcium mobilisation was induced in some mesothelium-derived cell lines by bradykinin. Des-Arg(9)-bradykinin was inactive, indicating that mesothelial cells are responsive to bradykinin, mediated via the bradykinin receptor subtype 2. In summary, pleural mesothelial cells support the assembly and activation of the plasma KKS by a mechanism dependent on HSP90, and may contribute to KKS-mediated inflammation in pleural disease.

In plain English

This laboratory study, which also measured bradykinin in human pleural fluid, asked whether mesothelial cells, the main cells lining the pleural cavity, can switch on the plasma kallikrein-kinin system, which produces the inflammatory molecule bradykinin. It did not study asbestos exposure. Bradykinin was found in all pleural fluid samples. In a UK group (8 malignant effusions, 6 benign exudates and 5 transudates), the median level was 62.1 ng/ml in exudates versus 24.2 ng/ml in transudates. In an Australian group of 40 patients, pleural fluid levels were higher than in matching blood serum in 18 of 40 cases. Levels did not differ significantly between benign and malignant effusions. Both groups included patients with malignant mesothelioma. All mesothelial and mesothelioma cell lines tested activated the system and released bradykinin. Novobiocin, an inhibitor of heat shock protein 90 (HSP90), was among the substances that strongly blocked this activation. The authors concluded that mesothelial cells likely contribute to the bradykinin found in pleural effusions. They said studies in living subjects are needed.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (in vitro) study using mesothelial and mesothelioma cell lines and primary cells, combined with measurement of bradykinin in human pleural fluid and serum samples from two patient cohorts
• Who was studied: Pleural fluid from two patient cohorts. The UK (Oxford) cohort: 8 malignant effusions (5 metastatic pleural adenocarcinomas, 3 malignant mesotheliomas), 6 benign exudates and 5 transudates. The Australian Mesothelioma Tissue Bank cohort: 20 patients with malignant effusions (including 10 malignant mesothelioma) and 20 with benign effusions, with paired serum. Cells studied: SV40-transformed MeT-5A mesothelial cells; malignant NCI-H28, NCI-H2052 and MSTO-211H cells; A549 cells; primary murine mesothelial cells from C57BL/6 mice; and primary mesothelioma cells from one 68-year-old man with pleural mesothelioma. Collection dates are not given.
• Exposure: No asbestos exposure was studied. Cells were treated with high molecular weight kininogen (HK) and plasma prekallikrein (PPK), with patients' pleural effusion fluids, with a panel of inhibitors, and with bradykinin or des-Arg9-bradykinin.
• Main results:
  • In the UK cohort, median bradykinin was 2.6-fold higher in exudates than in transudates (62.1 vs. 24.2 ng/ml; p = 0.025).
  • In the Australian paired cohort, bradykinin was higher in pleural fluid than in the corresponding serum in 18/40 (45%) cases, and 10 to 30-fold greater in some samples.
  • Bradykinin concentrations did not differ significantly between benign and malignant pleural effusions in either cohort.
  • All mesothelial and mesothelioma cell types treated with HK and PPK released bradykinin (p less than 0.0001 for all).
  • MeT-5A cells incubated with malignant pleural effusions showed higher plasma kallikrein activity than cells incubated with benign effusions (median absorbance 0.30, 25th to 75th quartile 0.26 to 0.32, vs. 0.23, 0.17 to 0.26; reported as significant at p = 0.04).
  • MeT-5A, NCI-H28 and NCI-H2052 cells showed HSP90 (beta form) on their surface. Weak staining for the alpha form was seen on MeT-5A cells.
  • Prolylcarboxypeptidase and Factor XII were not detected on the surface of these cells.
  • Activation on MeT-5A, NCI-H2052, NCI-H28 and primary murine mesothelial cells was strongly inhibited by cysteine, bradykinin, protamine sulphate and novobiocin (an HSP90 inhibitor). Angiotensin II, benzamidine and EDTA did not inhibit activation.
  • Bradykinin caused calcium influx in 20 to 25% of MeT-5A and NCI-H2052 cells but not in NCI-H28 cells. Des-Arg9-bradykinin had little effect on any cell line tested.
  • Unlike A549 cells, the mesothelial cell lines showed no change in IL-6 or IL-8 release after stimulation with bradykinin or des-Arg9-bradykinin.
• The authors' conclusion: The authors concluded that mesothelial cells and their matrix have the molecular machinery to activate the plasma kallikrein-kinin system, and that mesothelial cells likely contribute to the bradykinin found in pleural effusions.
• Limitations the authors state:
  • The study did not determine how much of the bradykinin in pleural fluid comes from mesothelial cells.
  • Future studies are needed to assess whether these processes contribute to bradykinin release in living subjects (in vivo).
  • Finding bradykinin in pleural effusions does not by itself prove it has a role in pleural inflammation.
  • The effect of novobiocin on purified plasma kallikrein could not be examined because a precipitate formed.

Topics

Medical terms in this study, explained in our Lexicon: Mesothelial Cells, Inflammation, Pleural Effusion, Pleural Cavity, Mesothelioma, Mesothelium.

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