Inflammation Inflammation is a well-known and critical

Inflammationis a complex biological process and localized tissue response thatoccurs in response to harmful stimuli or actual injury andwhose function is to eliminate the cause of cell injury and initiate the repairprocess which is the first physiological defense thatprotects the body from infection, burns, allergic factors,toxic chemical agentsand 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 affectedtissue (2, 3). Inflammation is awell-known and critical component in most lung diseases, such as acute lung injury, bronchiolitisobliterans, acuterespiratory distress syndrome, chronicobstructive pulmonary disease and cystic fibrosis (4).

Bacterial, viralpathogens 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 theouter membrane of most of the Gram-negative bacteria. The external surface ofthe LPS leads to a relationship between the bacteria and its environment, andits structure contributes to the stability and selectivity of the outermembrane. It can initiate a strong immune response and serves as an earlywarning signal of bacterial infection. LPS is initially extracted frombacterial membranes and vesicles released from them by LPS binding protein(LBP) in serum. LBP then transfers LPS to CD14, which can be found either insoluble form or linked to the cell surface by a glycosylphosphatidylinositolanchor (5, 6).

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By attachingLPS through a LPS-bound protein(LBP), the phosphatidylinositol glycan attachedto the cell membrane and CD14, to the TLR4 receptor (found in macrophages andendothelial cells), activates MyD88 and MAL signaling pathways. By activatingthese pathways, the important molecules involved in intracellular signaling,including ERK1/2, p38MAPK, JNK, phosphorylated, and activated. Byphosphorylation of these factors, leads to activation of NF-?B and its entryinto the cell nucleus (7). It then bindsto the targeting elements of the target genes that contain the pre-inflammatorygenes and causes the cell’s response to LPS by increasing the levels ofpre-inflammatory factors, including IL-1?, IL-6 and TNF-?, and increasing thelevels of COX-2 and iNOS (8, 9).The imbalance betweenpro-inflammatory and anti-inflammatory cytokines plays an important role invarious diseases (10). Cytokines are solubleproteins that play a key role in immune cell sigilation and inflammatoryresponses against microorganisms.

Some cytokines such as IL-1, IL-6 and TNF-?are considered as proinflammatory cytokines, however IL-10 and IL-4 areanti-inflammatory cytokines (11). LPS causes inflammatory conditions byactivating enzymes involved in oxidative stress such as nicotinamide adeninedinucleotide 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 thatresult from normal aerobic metabolism (7).Oxidative stress is caused byimbalance between oxidant-antioxidant systems, which could be because ofelevated 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 toinflammation by several inflammatory signaling cascades (13).Therefore, LPS with the described mechanisms, can causessystemic inflammation. The development and persistence of systemic inflammationcan also leads lung tissue damage. The renin-angiotensin system (RAS), historically, hasonly been used to regulate blood volume, peripheral blood vessels, and bloodpressure, but recent studies indicate that the renin-angiotensin system isassociated with other biological processes, such as inflammation, vascularreconstruction and apoptosis (14). Angiotensin II is an octapeptide that isinvolved in several stages of the inflammation process, so this peptide isconsidered as a real cytokine. Angiotensin II is an angiotensinogen protein that is converted by reninto angiotensin I.

An angiotensin converting enzyme (ACE) convertsangiotensin I into angiotensin II (15). Acrosing to findings from the last studies, theRAS also plays a critical role locally in various tissues and organs. Studiesof ACE mRNA distribution and enzymatic activity in rodent and human tissuesconfirmed the hypothesis of complete local tissue related to  RAS activity (16, 17). Captopril is an ACE inhibitor, initiallyapproved to treat high blood pressure and can be used alone or in combinationwith other antihypertensive drugs. New research has shown that captopril has antioxidant andanti-inflammatory properties apart from its effects on blood pressure andhemodynamic system, which can also be used for inflammatory diseases (18, 19) .Inthis study, the protective effects and potential mechanism of captopril, aknown ACE inhibitor, on LPS-induced lung inflammation was examined.


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