Inflammation Inflammation is a well-known and critical

is a complex biological process and localized tissue response that
occurs in response to harmful stimuli or actual injury and
whose function is to eliminate the cause of cell injury and initiate the repair
process which is the first physiological defense that
protects the body from infection, burns, allergic factors,toxic chemical agents
and other harmful stimuli (1).This process characterized by the release of cytokines,
chemokines and growth factors and by the transmigration of inflammatory cells,
such as neutrophils, monocytes and lymphocytes, from the blood to the affected
tissue (2, 3). Inflammation is a
well-known and critical component in most lung diseases, such as acute lung injury, bronchiolitis
obliterans, acute
respiratory distress syndrome, chronic
obstructive pulmonary disease and cystic fibrosis (4). Bacterial, viral
pathogens and environmental pollutants can cause lung inflammation (1).To mimic the course of inflammation,
various models have been developed. In this study we used LPS model to induce systemic inflammation.

Lipopolysaccharide (LPS)
is a well-characterized pathogen-associated molecular pattern found in the
outer membrane of most of the Gram-negative bacteria. The external surface of
the LPS leads to a relationship between the bacteria and its environment, and
its structure contributes to the stability and selectivity of the outer
membrane. It can initiate a strong immune response and serves as an early
warning signal of bacterial infection. LPS is initially extracted from
bacterial membranes and vesicles released from them by LPS binding protein
(LBP) in serum. LBP then transfers LPS to CD14, which can be found either in
soluble form or linked to the cell surface by a glycosylphosphatidylinositol
anchor (5, 6). By attaching
LPS through a LPS-bound protein(LBP), the phosphatidylinositol glycan attached
to the cell membrane and CD14, to the TLR4 receptor (found in macrophages and
endothelial cells), activates MyD88 and MAL signaling pathways. By activating
these pathways, the important molecules involved in intracellular signaling,
including ERK1/2, p38MAPK, JNK, phosphorylated, and activated. By
phosphorylation of these factors, leads to activation of NF-?B and its entry
into the cell nucleus (7). It then binds
to the targeting elements of the target genes that contain the pre-inflammatory
genes and causes the cell’s response to LPS by increasing the levels of
pre-inflammatory factors, including IL-1?, IL-6 and TNF-?, and increasing the
levels of COX-2 and iNOS (8, 9).

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The imbalance between
pro-inflammatory and anti-inflammatory cytokines plays an important role in
various diseases (10). Cytokines are soluble
proteins that play a key role in immune cell sigilation and inflammatory
responses against microorganisms. Some cytokines such as IL-1, IL-6 and TNF-?
are considered as proinflammatory cytokines, however IL-10 and IL-4 are
anti-inflammatory cytokines (11).

LPS causes inflammatory conditions by
activating enzymes involved in oxidative stress such as nicotinamide adenine
dinucleotide phosphate oxidase, nitric oxide synthase, xanthine oxid reductase,etc.
Superoxide anion (-O2), hydrogen peroxide (H2O2),
hydroxyl anion (OH-), and nitric oxide anion are free radicals that
result from normal aerobic metabolism (7).Oxidative stress is caused by
imbalance between oxidant-antioxidant systems, which could be because of
elevated free radical generation and decreased activity of antioxidants (12). Reactive oxygen species (ROS)
also has an important role in inflammation processes. On the other hand,
oxidative stress induces over production of ROS, that contribute to
inflammation by several inflammatory signaling cascades (13).Therefore, LPS with the described mechanisms, can causes
systemic inflammation. The development and persistence of systemic inflammation
can also leads lung tissue damage.

The renin-angiotensin system (RAS), historically, has
only been used to regulate blood volume, peripheral blood vessels, and blood
pressure, but recent studies indicate that the renin-angiotensin system is
associated with other biological processes, such as inflammation, vascular
reconstruction and apoptosis (14). Angiotensin II is an octapeptide that is
involved in several stages of the inflammation process, so this peptide is
considered as a real cytokine. Angiotensin II is an angiotensinogen protein that is converted by renin
to angiotensin I. An angiotensin converting enzyme (ACE) converts
angiotensin I into angiotensin II (15). Acrosing to findings from the last studies, the
RAS also plays a critical role locally in various tissues and organs. Studies
of ACE mRNA distribution and enzymatic activity in rodent and human tissues
confirmed the hypothesis of complete local tissue related to  RAS activity (16, 17). Captopril is an ACE inhibitor, initially
approved to treat high blood pressure and can be used alone or in combination
with other antihypertensive drugs. New research has shown that captopril has antioxidant and
anti-inflammatory properties apart from its effects on blood pressure and
hemodynamic system, which can also be used for inflammatory diseases (18, 19) .

this study, the protective effects and potential mechanism of captopril, a
known ACE inhibitor, on LPS-induced lung inflammation was examined.


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