1-INTRODUCTION
Proton pump inhibitors (PPI) are among the most commonly used medications in the world. With the initiation of use of the first PPI, omeprazole, at the end of 1980, PPIs were proven to be an effective treatment choice for a variety of diseases linked to acid including gastroesophageal reflux disease, peptic ulcer disease, Helicobacter pylori eradication treatment, dyspepsia and stress (Luo., Fan et al., 2018). The use of PPIs rose by 450% toward the end of the 1990s (Guda., Noonan et al., 2004). Currently we see many publications related to unnecessary and increasing rates of PPI use. A study in Spain observed high frequency of PPI use during hospital admission of patients and in the period after discharge (R). Additionally, in the period after discharge, PPI use continued with no indications for nearly 3-6 months. Use with the aim of preventing possible harmful effects of a variety of medications on the stomach is excessive. PPI group medications are known as stomach protectors among the public. People participating in a survey in research encompassing many countries around the world identified nearly 30% had acid indigestion, heartburn and reflux complaints (Luo., Fan et al., 2018). According to the results of the same study, the medications used to treat these people were mainly proton pump inhibitors. People using PPIs for many years are told that these medications only affect the stomach and have no effect on other tissues or organs and that they can use them comfortably. As a result, excessive amounts of use are present.
In the past PPIs were frequently used for patients being treated in intensive care units with frequent multiple drug use. During use by these types of patients, it was predicted to affect patient mortality, so the use of H2 receptor blockers was recommended in these cases (Hamai., Iwamoto et al., 2018). Deaths occurring due to the use of PPIs in patients treated in intensive care occurred due to bacterial proliferation linked to the stomach pH becoming alkali and bacteria reaching the lungs causing infections, with patients proposed to have died due to lung infections (Hamai., Iwamoto et al., 2018; ; Garvey., McCambley et al.,1989). However, the H2 receptor blockers used as alternative treatments also make the stomach pH alkali. Though both medications increase stomach pH, the effect mechanisms are different. The effects of PPIs are shown through acid pH. If the pH of body cells and tissues do not remain within physiologic limits, it is not compatible with life; as a result, if pH doesn’t fall PPIs do not become active and it is proposed they have no effects outside the stomach. It is not fully clear which mechanism forms a variety of side effects of PPIs. In vitro studies have revealed reduced neutrophil bactericidal activity caused by omeprazole (Zedtwitz-Liebenstein., Wenisch et al., 2002). Different to previous explanations related to pneumonia occurring as a result of PPI use and resulting deaths, our thoughts are as follows; the most important effect mechanism in the struggle between leukocytes, especially neutrophil leukocytes, with bacteria are degradation and digestion of phagocytic bacteria by lysosomes. The pH within lysosomes is very acidic. For degradation and digestion of bacteria within lysosomes, hydrogen peroxide (H2O2) should form within lysosomes and the H2O2 should later be transformed into hypochlorous acid (HOCl). For creation of H2O2 in lysosomes, H must be taken inside the lysosomes. In order for H to be taken into lysosomes, a proton pump must be used. After long-term PPI use, the proton pumps in lysosomes are inhibited which means the struggle between neutrophil leukocytes with bacteria will not provide results.
In light of these findings, in our study we attempted to research the possible effect mechanisms of PPIs on some tissues and cells outside the stomach and to reveal the cause of side effects proposed to be caused by proton pump inhibitors and our hypothesis. With this aim, lung tissues from experimental animals were stained with catalase (CAT), myeloperoxidase (MYP), superoxide dismutase (SOD) and glutathione peroxidase (Gpx) stains in an attempt to observe the activities of these enzymes. Additionally, lung tissues were investigated with an electron microscope to assess morphologic changes. These enzymes effective on oxidative stress and antioxidant mechanisms are some of the parameters required to prove our thesis. SOD is a 32 KDa hemodimeric metalloenzyme basically found in plasma, nucleus and cytosol (Chen., Watson et al., 2017). It catalyzes the differentiation of a catalytic copper ion and superoxide radical into dioxygen and H2O2. Extracellular SOD is released and synthesized by fibroblast cells, glial cells, and endothelial cells. Lung tissue has high extracellular SOD levels. SOD is the only antioxidant which can inactivate enzymatic free oxygen radicals at extracellular level. As a result, extracellular SOD undertakes important duties in terms of protecting against diseases like oxidant injury, inflammation and fibrosis (Gao., Kinnula et al., 2008). SOD increases efficacy when the organism experiences increased oxidant stress. Especially in clinical situations with reduced effect of antioxidant systems, SOD activity increases (Rahimi., Rakhshandeh et al.,2019; Limon Pcheco and Gonsebatt., 2009). In our study, in parallel with this knowledge, SOD activity was observed to increase in lungs.
Gpx is the most effective enzyme in endothelial cells, especially in lung (Cheeseman and Slater.,1993). Free radicals are highly reactive species damaging DNA in proteins, lipids and carbohydrates causing structural cell injury and apoptosis. Exogenous antioxidant enzymes like CAT, SOD, Gpx, MYP and thiol groups protect against oxidative stress injury caused by free radicals (Sheng., Abreu et al., 2014).
Additionally, we researched whether the H2O2 levels found in lung tissues were different between the groups. Clinical research in the recent period has shown significant side effects of this medication group; however, it has still not been fully revealed which effect mechanism causes the occurrence of these side effects.