Volume 15 Supplement 3

Sepsis 2011

Open Access

Sepsis-induced lung fibrosis in baboons is reduced by the treatment with a complement inhibitor

  • F Lupu1, 2,
  • H Zhu1,
  • R Silasi-Mansat1,
  • C Georgescu3,
  • N Popescu1,
  • G Peer4,
  • C Lupu1,
  • F Taylor1, 2,
  • G Kinasewitz4 and
  • J Lambris5
Critical Care201115(Suppl 3):P34

DOI: 10.1186/cc10403

Published: 27 October 2011

Introduction

Pulmonary fibrosis is a major and common medical condition, characterized by progressive scaring and decline in lung function. Persistent inflammation and acute lung injury in response to sepsis are potential triggers of the fibrotic response. Recently, we have reported that Escherichia coli sepsis in baboons strongly induces procoagulant responses and affects the integrity of the lung. These effects are diminished by the treatment with compstatin, a C3 convertase complement inhibitor [1].

Methods

Here we used the baboon model described [1] in conjunction with detailed gene expression analysis, as well as biochemical and histological assays to determine if E. coli sepsis triggered metabolic and signaling pathways related to lung remodeling and fibrosis, and whether complement inhibition could attenuate these pathways.

Results

Microarray gene expression analysis shows that sepsis augments several fibrotic gene clusters in the lung as early as 24 hours post E. coli challenge. Immunochemical and biochemical analysis reveals enhanced collagen synthesis, induction of profibrotic factors and increased cell recruitment and proliferation. Compstatin treatment decreases sepsis-induced expression of extracellular matrix genes, including eight collagen genes. Sirius Red and immunofluorescence staining for procollagens 1 and 3 confirms the collagen deposition in the lung. Ingenuity® pathway analysis of transcriptomics data shows that compstatin treatment reduces sepsis-induced expression of genes involved in fibroblast transformation and connective tissue production, cell chemotaxis, migration and proliferation (see Table 1). Immunocytochemistry and pathway-oriented transcriptomics and phospho-proteomics analysis reveal changes of multiple processes mediated by transforming growth factor beta (TGF-β), connective tissue growth factor and other TGF-β controlled proteins. Immunostaining for cell proliferation markers demonstrates that compstatin treatment strongly reduces cell proliferation in fibroblastic foci. Moreover, biochemical analysis shows decreased production in the compstatin-treated group of two chemokines responsible for fibrocyte recruitment (CCL2 and CXCL12) and of the type 1 tissue inhibitor of metalloproteases that controls extracellular matrix remodeling.
Table 1

abstract P34

 

E. coli

E. coli+ CS T+5

 

Modified genes

 

Modified genes

 
 

Up

Down

Total

P value

Up

Down

Total

P value

Fibroblast transformation

32

10

42

1.41 × 10-6

12

69

81

1.09 × 10-7

Connective tissue disorder

133

59

192

2.62 × 10-5

92

341

434

3.1 × 10-7

Chemotaxis

39

13

52

5.0 × 10-3

31

92

123

1.98 × 10-5

Cell migration

95

40

135

2.11 × 10-5

80

250

330

9.36 × 10-8

Cell proliferation

187

70

257

2.67 × 10-8

118

466

584

5.83 × 10-13

Fibroblast proliferation

23

7

30

4.80 × 10-3

10

62

72

5.56 × 10-6

CS T+5, compstatin-treated animals at T + 5 hours.

Conclusion

Our data demonstrate that bacterial sepsis initiates pulmonary collagen deposition, and complement inhibition effectively attenuates the fibrotic response. This suggests that complement inhibitors could be used for prevention of sepsis-induced pulmonary fibrosis.

Declarations

Acknowledgements

The authors thank Dr Bart Frank (OMRF) for help with protein array scanning and quantitation. This work was supported by grants from the National Institutes of Health (GM097747-01 to FL and JL; 2P20RR018758-06A2 and 1RC1GM09739-02 to FL; AI068730 and GM062134 to JL).

Authors’ Affiliations

(1)
Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation
(2)
Department of Pathology, Oklahoma University Health Sciences Center
(3)
Neuroscience Research Department, Mayo Clinic
(4)
Department of Medicine, Pulmonary and Critical Care Division, Oklahoma University Health Sciences Center
(5)
Department of Pathology and Laboratory Medicine, School of Medicine, University of Pennsylvania

References

  1. Silasi-Mansat R, Zhu H, Popescu NI, Peer G, Sfyroera G, Magotti P, Ivanciu L, Lupu C, Mollnes TE, Taylor FB, et al.: Complement inhibition decreases the procoagulant response and confers organ protection in a baboon model of Escherichia coli sepsis. Blood 2010, 116: 1002-1010. 10.1182/blood-2010-02-269746PubMed CentralView ArticlePubMedGoogle Scholar

Copyright

© Lupu et al. 2011

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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