Effects of the Novel Pharmacological Compaou nd Sul-121 on LPS-Induced Airway Neutrophilia

    Han B. | Rijks Universiteit Groningen | 22 augustus 2016 |

As a nonprofit organization, the American Thoracic Society (ATS) improves global health by advancing research, patient care, and public health in pulmonary disease, critical illness, and sleep disorders. ATS is focusing on improving care for pulmonary diseases, critical illnesses and sleep-related breathing disorders. Founded in 1905, the ATS has grown to tackle asthma, COPD, lung cancer, sepsis, acute respiratory distress, and sleep apnea, among other diseases. The ATS International Conference is where researchers, clinicians and related healthcare professionals from around the world meet to learn the latest advances in respiratory, critical care, and sleep medicine. Almost 44 percent of conference attendees are from outside the United States. We come because the opportunities to learn, network, share ideas and grow professionally are unequaled anywhere else. Below are the report of my study which has been released during ATS2016, followed by several useful points that I gathered form this conference.

Chronic obstructive pulmonary disease (COPD) is one of the leading causes of death worldwide, which results a significant economic and social burden (GOLD 2015). It is characterized by persistent and progressive airflow limitation and prominent neutrophilic airway inflammation (Hoenderdos and Condliffe 2013; GOLD 2015). Currently, reduction of COPD symptoms is achieved mainly with (a combination of) anticholinergics, β2-adrenoceptor agonists and glucocorticosteroids (GOLD 2015). However, the current medications fail to reduce the progression of COPD and have even been associated with fatal side effects (Barnes et al. 2003; Broadley 2006; Barnes 2008; Matera et al. 2014).

Oxidative stress, caused by an anti-oxidant/oxidant imbalance that leads to increased generation of reactive oxygen species (ROS), is believed to play an important role in the pathogenesis of COPD (Kirkham and Barnes 2013). ROS exert profound effects in the lungs due to their direct and constant exposure to an environment with a higher oxygen load (Kirkham and Barnes 2013). ROS derived from exogenous (environmental pollution, cigarette smoke) or endogenous (inflammatory cells, such as neutrophils) insult, promote pulmonary oxidative stress and contribute to the development and progression of COPD (Kirkham and Barnes 2013). ROS promote the activation of the pro-inflammatory transcription factor nuclear factor (NF)-κB in structural lung cells including airway smooth muscle cells (Luo et al. 2009). Activation of NF-κB results in increased secretion of inflammatory cytokines such as interleukin (IL)-8 (Oenema et al. 2010; Oldenburger et al. 2012; Pera et al. 2012), which recruit inflammatory cells, including neutrophils (Barnes 2008). Moreover, ROS trigger the peroxidative breakdown of lipids, a process implicated in lung injuries due to increased airway epithelial permeability (Shintani et al. 2015). ROS have also been implicated as an important cause of steroid resistance in COPD (Barnes 2013). Targeting oxidative stress might be a beneficial approach for the management of COPD. Currently, anti-oxidative strategies have chiefly been limited to include the use of anti-oxidants or pharmacological agents known to increase the endogenous antioxidant level (Rahman 2006). Although evidence for clear clinical benefits is currently lacking, many of these strategies have shown promising effects by increasing the antioxidant capacity in COPD (Kirkham and Barnes 2013).

Due to its anti-oxidative capacities, hydrogen sulfate (H2S) has been proposed as a potential COPD treatment (Faller et al. 2012). The gasotransmitter H2S is synthesized by enzymes such as cystathionine β synthetase (CBS) and its anti-oxidative capacities are mainly attributed to its high redox potential (Chen and Wang 2012). By contrast, some studies indicated that its redox potential may provoke pro-inflammatory responses, for instance, oxidative stress originated from activated neutrophils can convert H2S to sulfite (Mitsuhashi et al. 2005), which is considered an inflammatory mediator in airway diseases (Mitsuhashi et al. 2004). Therefore, the usage of H2S or its donors to treat COPD is still under debate.
One mechanism that could underpin an anti-oxidant response to H2S is the activation of nuclear factor erythroid 2-related factor 2 (Nrf2), a transcription factor that increases the expression of anti-oxidant proteins in structural airway cells, including smooth muscle cells (Michaeloudes et al. 2011; Shintani et al. 2015). Indeed, H2S is able to activate Nrf2 both in vivo in mouse models of lung injury and in vitro in embryonic fibroblasts (Han et al. 2011; Francis et al. 2011; Hourihan et al. 2013).

Recently, we developed a novel class of pharmacological compounds of which Sul-121 (6-hydroxy-2,5,7,8-tetramethylchroman-2-yl (piperazin-1-yl) methanone hydrochloric acid) is one of its leads with promising cell protective effects due to anti-oxidant capacities(Van der Graaf et al. 2014). In the present study, we explored the pharmacological potential of Sul-121 in in vitro and in vivo experimental models of COPD. We report that Sul-121 prevents lipopolysaccharide (LPS)-induced neutrophilia, hyperresponsiveness (AHR) and oxidative stress in guinea pigs. In addition, Sul-121 reduces the cigarette smoke-induced release of IL-8 in cultured human airway smooth muscle (ASM) cells, which is accompanied by a reduction in cellular ROS production and nuclear translocation of Nrf2.

We reported that Sul-121 prevented LPS-induced airway neutrophilia in both cartilaginous and non-cartilaginous airways. Blood neutrophils were not significantly altered by either LPS, Sul-121 or their combination. Although the expression of Nrf2 was not changed by either LPS, Sul-121 or their combination, Sul-121 exerted anti-oxidative capacity by preventing LPS-induced production of MDA in lungs. Moreover, MDA level positively correlated with airway neutrophil numbers. In line with these findings, Sul-121 diminished ROS levels in solutions of H2O2 or cigarette smoke extract, as well as phorbol 12-myristate 13-acetate-induced cellular ROS production in ASM cells.

Taken together, our data show that Sul-121 effectively inhibits LPS-induced airway neutrophilia in guinea pigs, likely through prevention of oxidative stress. Therefore, Sul-121 may represent a potential candidate for the pharmacological treatment of COPD.
During the conference, many people showed interest to our study. I also gathered several information that may be helpful to our Sul-121 study. I have discussed with many scientist in the field. They provide valuable information for our future studies. I attended the course “ROLE OF VITAMIN D IN ASTHMA AND ABPA”, where it focuses on the role of vitamin D in the pathogenesis of asthma and ABPA. On the basis of previous studies and our research findings in the field of vitamin D and T regulatory cells expression in children with asthma, the future prospects of using vitamin D as adjuvant therapy in asthma and ABPA will be discussed.
In conclusion, with all the interesting workshops and lectures on the conference, I learned knowledge and exchanged ideas with all my international counterparts. Attending to this conference also helped to extend my connection internationally.

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Keyword: ATS 2016 COPD Oxidative stress

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