Peripheral 5-HT7 receptors as a new target for prevention of lung injury and mortality in septic rats

Abstract

Sepsis is a complex pathophysiological event involving metabolic acidosis, systemic inflammatory response syndrome, tissue damage and multiple organ dysfunction syndrome. Although many new mechanisms are being investigated to enlighten the pathophysiology of sepsis, there is no effective treatment protocol yet. Presence of 5-HT7 receptors in immune tissues prompted us to hypothesize that these receptors have roles in inflammation and sepsis. We investigated the effects of 5-HT7 receptor agonists and antagonists on serum cytokine levels, lung oxidative stress, lung histopathology, nuclear factor κB (NF-κB) positivity and lung 5-HT7 receptor density in cecal ligation and puncture (CLP) induced sepsis model of rats. Agonist administration to septic rats increased survival time; decreased serum cytokine response against CLP; decreased oxidative stress and increased antioxidant system in lungs; decreased the tissue NF-κB immunopositivity, which is high in septic rats; and decreased the sepsis-induced lung injury. In septic rats, as a result of high inflammatory response, 5-HT7 receptor expression in lungs increased significantly and agonist administration, which decreased inflammatory response and related mortality, decreased the 5-HT7 receptor expression.

In conclusion, all these data suggest that stimulation of 5-HT7 receptors may be a new therapeutic target for prevention of impaired inflammatory response related lung injury and mortality.

Introduction

Sepsis is one of the most prevalent diseases and one of the main causes of death among hospitalized patients (Alberti et al. 2002). Sepsis/septic shock is a complex pathophysiological event characterized by profound hypotension, progressive metabolic acidosis, systemic inflammatory response syndrome, tissue damage and multiple organ dysfunction syndrome, acute respiratory distress syndrome (ARDS) and/or acute lung injury (ALI) and even death (Ozdulger et al. 2003). Although its pathophysiology is not well defined, monocytes orchestrate the innate immunity response to bacteria by expressing a variety of inflammatory cytokines; in particular, early TNF-α, IL-1β and IL-6 are considered to participate prominently in the pathogenesis of sepsis (Moine and Abraham 2004). Nuclear factor κB (NF-κB) is an inducible nuclear transcription factor that plays a central role in regulating the transcription of several genes, including those that encode the proinflammatory cytokines (Shen et al., 2009, Tergaonkar, 2006) such as TNF-α, IL-1β, IL-6, adhesion molecules and additional proinflammatory mediators involved in severe sepsis, septic shock, ARDS and ALI (Bone, 1991, Hotchkiss and Karl, 2003). Proinflammatory cytokines induce release of secondary cytokines, lipid mediators and reactive oxygen species (ROS). In recent studies, oxidative stress has been shown to play an important role in sepsis-related mortality and organ dysfunction (Cadirci et al., 2010a, Uyanik et al., 2010, Albayrak et al., 2011).

Although many new mechanisms are being investigated to enlighten the pathophysiology of sepsis, there is no effective treatment protocol yet. In the literature, there is a sizeable body of clinical and experimental studies focusing on pathophysiology and treatment of sepsis, showing the popularity and importance of this issue. After a detailed literature search, we decided to investigate serotonin receptors, especially 5-HT7, in sepsis.

Serotonin (5-hydroxytryptamine, 5-HT) is a biogenic monoamine with a variety of functions in many physiological and pathophysiological processes (Yang et al. 2006). It is well established that various biological effects of 5-HT are mediated through different serotonin receptors and their signal transduction pathways (MaassenVanDenBrink et al. 2008). Being among the most recently discovered receptors for serotonin, the 5-HT7 receptor is also one of the least well characterized (Hedlund et al., 2004, Hedlund and Sutcliffe, 2004, Hedlund, 2009). Subsequent in situ hybridization studies, in both rats and guinea pigs, have confirmed that 5-HT7 receptor mRNA in the brain is found predominantly in the thalamus, hypothalamus, cerebral cortex, hippocampus and amygdala (Neumaier et al., 2001, To et al., 1995, Tsou et al., 1994). However, studies about peripheral effects of these receptors are limited. These receptors have been shown in arteries such as pulmonary, coronary arteries and aorta (Nilsson et al., 1999, Ullmer et al., 1995). The presence of 5-HT7 receptors has been shown in T cells: 5-HT7 receptor stimulation contributes in T-cell functions and activations (Leon-Ponte et al. 2007). Soga et al. showed that 5-HT prevents monocytic apoptosis by 5-HT7 and/or 5-HT7 receptors (Soga et al. 2007). Stefuj et al. showed presence of 5-HT7 receptor mRNA in both human and rat immune tissues such as thymus, spleen, peripheral lymphocytes and mitogen-activated spleen cells (Stefulj et al. 2000). Presence of 5-HT7 receptors in both human (Heidmann et al. 1997) and rat (Stefulj et al., 2000, Shen et al., 1993) immune tissues prompted us to hypothesize that these receptors have roles in immune response in inflammation and sepsis. However, there is no study investigating the effects of 5-HT7 receptors in sepsis and sepsis-induced lung damage.

In light of the above data, this study aimed (1) to investigate the possible role of 5-HT7 receptors in cecal ligation and puncture (CLP) induced polymicrobial sepsis model, (2) to determine 5-HT7 receptor presence in lung tissue, which is important in sepsis-related mortality, and (3) to observe the effects of 5-HT7 receptor agonist and antagonist administration on normal progress of sepsis.