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.