Restoration of lung surfactant protein D by IL-6 protects against secondary pneumonia following hemorrhagic shock

Abstract

Summary Objectives To identify novel approaches to improve innate immunity in the lung following trauma complicated by hemorrhagic shock (T/HS) for prevention of nosocomial pneumonia. Methods We developed a rat model of T/HS followed by Pseudomonas aeruginosa (PA) pneumonia to assess the effect of alveolar epithelial cell (AEC) apoptosis, and its prevention by IL-6, on lung surfactant protein (SP)-D protein levels, lung bacterial burden, and survival from PA pneumonia, as well as to determine whether AEC apoptosis is a consequence of the unfolded protein response (UPR). Lung UPR transcriptome analysis was performed on rats subjected to sham, T/HS, and T/HS plus IL-6 protocols. Group comparisons were performed via Kaplan–Meier or ANOVA. Results T/HS decreased lung SP-D by 1.8-fold (p < 0.05), increased PA bacterial burden 9-fold (p < 0.05), and increased PA pneumonia mortality by 80% (p < 0.001). IL-6, when provided at resuscitation, normalized SP-D levels (p < 0.05), decreased PA bacterial burden by 4.8-fold (p < 0.05), and prevented all mortality from PA pneumonia (p < 0.001). The UPR transcriptome was significantly impacted by T/HS; IL-6 treatment normalized the T/HS-induced UPR transcriptome changes (p < 0.05). Conclusions Impaired innate lung defense occurs following T/HS and is mediated, in part, by reduction in SP-D protein levels, which, along with AEC apoptosis, may be mediated by the UPR, and prevented by use of IL-6 as a resuscitation adjuvant.

Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 to Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution

“…In addition, administration of a NO scavenger also resulted in reduced lung injury and reduced activation of NF-kB and STAT3 after resuscitated hemorrhagic shock (Hierholzer et al, 2002), presumably through downregulation of acute inflammation (Hierholzer et al, 2002). Importantly, resuscitation from hemorrhagic shock also resulted in apoptosis of lung type I alveolar endothelial cells (Moran et al, 2009), liver hepatocytes (Moran et al, 2008), and cardiomyocytes (Thacker et al, 2013), which resulted in increased susceptibility to pneumonia (Thacker et al, 2014) and sepsis following intraperitoneal bacterial challenge (Arikan et al, 2006). Importantly, apoptosis of these critical parenchymal cells in the lung, liver, and heart and the increased susceptibility to pneumonia and bacterial peritonitis could be reversed by administration of IL-6 at the start of resuscitation; this action of IL-6 was mediated by activation of STAT3.…”

Deficiency of the Two-Pore-Domain Potassium Channel TREK-1 Promotes Hyperoxia-Induced Lung Injury

“…Previous studies have suggested that IL-6 is a multifunctional cytokine with time-, dose-and organ-specific functions[32]. For example, IL-6 is known to decrease T cell apoptosis and promote epithelial survival in the GI system[33], and to ameliorate lung injury by re-establishing surfactant levels[34]. Similarly, MCP-1 is known to play a protective role in bleomycin-induced lung injury[35].…”

Surfactant Protein D in Respiratory and Non-Respiratory Diseases

“…Additional potential treatments that have been suggested include the use of covalently bound complexes, comprising antibody crosslinked to point mutated SP-D ( 299 , 488 ), or introduction of specific N-linked glycans ( 489 ), in enhanced anti-viral or anti-bacterial therapies ( 490 ); for example, genetically engineered SP-D, which is resistant to proteolysis and relevant for the treatment of P. aeruginosa ( 250 , 260 ); reduction of lung inflammation and injury after allogeneic hematopoietic stem cell transplantation ( 491 ); inclusion of SP-D in nasal spray for chronic rhinosinusitis with polyps ( 13 ); alleviation of pneumonia severity and intestinal injury in Staphylococcus aureus pneumonia ( 441 ) or pulmonary aspergillosis ( 205 ). Moreover, therapeutic approaches have been suggested to increase transcription of SP-D ( 62 , 492 ).…”