Acute lung injury and fibrosis in a baboon model of Escherichia coli sepsis.

Abstract

Sepsis-induced inflammation of the lung leads to acute respiratory distress syndrome (ARDS), which may trigger persistent fibrosis. The pathology of ARDS is complex and poorly understood, and the therapeutic approaches are limited. We used a baboon model of Escherichia coli sepsis that mimics the complexity of human disease to study the pathophysiology of ARDS. We performed extensive biochemical, histological, and functional analyses to characterize the disease progression and the long-term effects of sepsis on the lung structure and function. Similar to humans, sepsis-induced ARDS in baboons displays an early inflammatory exudative phase, with extensive necrosis. This is followed by a regenerative phase dominated by proliferation of type 2 epithelial cells, expression of epithelial-to-mesenchymal transition markers, myofibroblast migration and proliferation, and collagen synthesis. Baboons that survived sepsis showed persistent inflammation and collagen deposition 6-27 months after the acute episodes. Long-term survivors had almost double the amount of collagen in the lung as compared with age-matched control animals. Immunostaining for procollagens showed persistent active collagen synthesis within the fibroblastic foci and interalveolar septa. Fibroblasts expressed markers of transforming growth factor-β and platelet-derived growth factor signaling, suggesting their potential role as mediators of myofibroblast migration and proliferation, and collagen deposition. In parallel, up-regulation of the inhibitors of extracellular proteases supports a deregulated matrix remodeling that may contribute to fibrosis. The primate model of sepsis-induced ARDS mimics the disease progression in humans, including chronic inflammation and long-lasting fibrosis. This model helps our understanding of the pathophysiology of fibrosis and the testing of new therapies.

• Authors: Ravi S Keshari, Robert Silasi-Mansat, Hua Zhu, Narcis I Popescu, Glenn Peer, Hala Chaaban, John D Lambris, Holly Polf, Cristina Lupu, Gary Kinasewitz, Florea Lupu
• Journal: American journal of respiratory cell and molecular biology (Am J Respir Cell Mol Biol) Vol. 50 Issue 2 Pg. 439-50 (Feb 2014) ISSN: 1535-4989 [Electronic] United States
• PMID: 24066737 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Transforming Growth Factor beta
• Collagen

Topics

• Acute Lung Injury (metabolism, physiopathology)
• Animals
• Collagen (metabolism)
• Disease Models, Animal
• Escherichia coli
• Fibrosis (metabolism)
• Humans
• Inflammation (metabolism, pathology)
• Lung (metabolism, pathology)
• Papio
• Respiratory Distress Syndrome (metabolism, pathology, physiopathology)
• Sepsis (metabolism, pathology)
• Signal Transduction (physiology)
• Transforming Growth Factor beta (metabolism)