Mechanisms responsible for surfactant changes in sepsis-induced lung injury

Abstract

Pulmonary surfactant is altered in sepsis, and these changes contribute to the predisposition of septic lungs to subsequent insults, ultimately leading to acute lung injury. Specifically, the total amount of surfactant is lower in sepsis, mainly due to decreased small aggregate (SA) surfactant pools. The amount of large aggregate (LA) surfactant is not altered.To evaluate the mechanisms responsible for these alterations, trace doses of tritium-labelled dipalmitoylphosphatidylcholine ( 3 H-DPPC)-labelled LA were instilled intratracheally into adult rats 20 hrs after caecal ligation and perforation (CLP) or sham surgery. Animals were sacrificed at 0, 1 and 4 h after instillation and recovery of 3 H-DPPC in alveolar macrophages (AM), LA and SA was measured. In separate in vitro experiments, AM isolated from CLP/sham rats were incubated with LA or SA isolated from normal animals to evaluate the uptake of these aggregates into the AM. Results showed increased surfactant radioactivity associated with AM of CLP animals compared with sham animals both in vivo and in vitro. In addition, more 3 H-DPPC label remained in LA forms in the CLP animals in vivo compared with sham.These findings indicate that differences in surfactant aggregate uptake and large aggregate conversion occur in septic lungs, resulting in changes in surfactant pools.

Ox‐LDL‐induced TGF‐β1 production in human alveolar epithelial cells: Involvement of the Ras/ERK/PLTP pathway

“…However, surfactant dysfunction, either due to a oxidizing environmental exposure or lung inflammation, may lead to reduced lung compliance and potentially increased lung edema formation in acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) (Kuzmenko et al, 2004;Davidson et al, 2005;Russo et al, 2007). Although exogenous surfactant replacement is of proven benefit in the prevention and treatment of infant respiratory distress syndrome (Jobe, 1993), the results of clinical trials evaluating surfactant administration in adults with ALI/ARDS is not optimistic (Anzueto et al, 1996;Spragg et al, 2004;Huang et al, 2005). This motivates us to elucidate the underlying molecular mechanisms regulating the development of surfactant dysfunction in early ALI.…”

Alveolar macrophage depletion is associated with increased surfactant pool sizes in adult rats

“…There is strong evidence that alterations to surfactant metabolism contribute to the lung dysfunction associated with various pulmonary diseases. More specifically, altered surfactant clearance by the AM has been implicated in the surfactant alterations associated with acute respiratory distress syndrome (ARDS) and pulmonary alveolar proteinosis (PAP) (21,28,49,50).…”

Contribution of alveolar macrophages to the response of the TIMP-3 null lung during a septic insult

“…The increase in compliance was accompanied by significantly decreased collagen and fibronectin levels but no changes to the pulmonary surfactant system, indicating that a rapid degradation of extracellular matrix components due to MMP activity was, in part, responsible for the effect (44,45). To further examine this phenomenon and since 1) the altered response of the TIMP-3 KO lung was specific to a septic insult, 2) alveolar macrophages are activated by the inflammatory cascade during sepsis (30,34,62), and 3) the main inflammatory cell found in the lungs of this model are alveolar macrophages, the main focus of this study was to determine whether depletion of alveolar macrophages in the TIMP-3 KO lung before the septic insult could prevent the alterations in pulmonary compliance.…”

“…The remaining lung tissue was snap frozen in liquid nitrogen for zymographic analysis. The lavage was centrifuged for 10 min at 400 g at 4°C for isolation of inflammatory cells within the lavage as previously described (30). The supernatant from this spin of the lavage was snap frozen in liquid nitrogen for cytokine analysis.…”