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To evaluate thepossible protective effects of captopril against LPS-induced lung inflammation,we measured the total and differential WBC, MDA, SOD, CAT, thiol levels and concentrationof IFN_?, PGE2, TGF-?1 and IL-4 in BALF. The LPS model is widely used and hasbeen shown to closely mimic the development of inflammation (21). The prolonged intraperitoneal LPS injection model are often usedto generate a systemic inflammatory response that comprises a more complicatedcondition, with interactions between the whole body and the lung (22).The result ofthis study show increas MDA concentration, total WBC, percent of neutrophils, basophilsand macrophages, concentration of IFN_?, PGE2, TGF-?1, as well as decreasedpercent of lymphocytes, total thiol groups, CAT and SOD activity in the BALF ofthe LPS group. .All these changes support occurrence of systemic inflammationand induction of an animal model of lung inflammation in rats.

Increased totalWBC, percent of neutrophils, macrophages and basophils in BALF of LPS groupcompared to control group observed in this study, which has been shown anddiscussed in previous studies (4, 23, 24).LPS by systemic inflammation, induced increase in total WBC and infiltration ofWBC into BALF andlung tissues. Of the most important Inflammatory cells involved in lung inflammationare neutrophils and macrophages, which release inflammatory mediators includingproteases, oxygen radicals and cytokines (25). Leakage of protein into the alveolar space and neutrophilsactivation and accumulation is the characteristic of lung inflammation (26). It is well known that LPS stimulates macrophages to sequentiallyrelease inflammatory cytokines including TNF-a and IL-6, which may participatein the development of inflammation (27). The decrease of lymphocytes percentage in the LPS group in thisstudy is mainly due to an increase in the total count of WBC, and if theabsolute count of lymphocytes is considered, it will be higher than the controlgroup as previous study (28, 29).

According tothe results of the present study, oxidative stress was significant increased inMDA and also decrease in total thiol groups and activity of catalase andsuperoxide dismutase enzymes in BALF of LPS group compared to the controlgroup, which is similar to the results of previous studies (30, 31). Oxidative stress results from imbalance betwenoxidant–antioxidant system with an increase of oxidants or a decrease ofantioxidants (31). In the pathogenesis of lung inflammation, Oxidative stress playan important role, not only through direct injurious effects, but also byinvolvement in the cellular and molecular mechanisms that control lunginflammation (32). Reactive oxygen species (ROS), such as the hydroxyl radical (OH)and the superoxide anion (O2) can cause damage and promoteinflammation. Against the damaging effects of O2, SOD is the primaryenzymatic defense in the lungs by converting O2 into H2O2 (32). H2O2 is then converted to water (H2O) by CAT (33).

ROS are highly reactive and can induce lipid peroxidation(oxidation of membrane phospholipids). MDA is a product of lipid peroxidationand its concentration has a positive correlation with reactive oxygen radicals (34). In the pathogenesis oflung inflammation, peroxidation of polyunsaturated fatty acids due to theeffects on cell membrane function, inactivation of membrane-bound receptors andenzymes, and increased tissue permeability (35).

Thiol groups are important antioxidants in the body and reducing ofthis antioxidants, leads to activation of NF-?B and increased transcription ofinflammatory genes (36).The results ofthis study, cytokine changes showed a significant increase in concentration of IFN_?,PGE2 and TGF-?1 as well as significant decrease in  concentration of IL-4  in BALF of LPS group compared with controlgroup which is compatible with previous studies (37, 38) .Proinflammatorycytokines such as tumor necrosis factor-a (TNF-a) and  interleukins (IL)-1 are critical linkersbetween the innate and adaptive cell-mediated immunity. They activate growthand differentiation of T- and B-lymphocytes, and macrophages, and thusinflammatory processes (39, 40). Interferon gamma is a pro-inflammatory cytokine that plays animportant role in providing antigens and activating T cells (41).  TGF-?1 is fibrogeniccytokine  that play important role in pathogenesisof lung inflammation and lung injury by various mechanisms, includinginhibiting activation and proliferation of immune cells, regulatingextracellular matrix, inducing apoptosis, inhibiting the production ofproteases, and stimulating the production of protease inhibitors. (42, 43).

COX-2 is thelargest PGE-2 synthesizer (44). LPS is a potent activator of inflammatorypathways with NF-?B activation. By activating NF-?B, the transcription of theisoenzyme gene of  COX-2 were increases,which increases the amount of PGE-2 (45).

Our result show decrease in  concentration ofIL-4 in LPS group however in studies that have been acutely investigated byLPS, the level of IL-4 has increased (11). IL-4  is anti-inflammatorycytokine. At the beginning of the inflammation, the body tries to suppressinginflammation process by increasing anti-inflammatory cytokines, but withprolonged and chronic inflammation, the body’s activity were impaired, so reducedanti-inflammatory cytokinesm1 .Result of this study demonstrated the protective effect of captopril onLPS-induced lung inflammation in rat. Captoprilsuppressed LPS-induced lung inflammation in rat and reduced inflammatorymarkers in the lung. Pretreatment and treatment with captopril in a dose dependent manner, significantlyreduced lung inflammation with decrease oxidative stress, total and percentageof WBC and inflammatory cytokines. These results indicated that,captopril reduced oxidative stress with decrease  MDA concentration and increase total thiolgroups and activity of SOD and CAT enzymes.

On the other hand captopril reducedconcentration of inflammatory cytokines (concentration of IFN_?, PGE2 and TGF-?1)and with improvement of inflammatory condition, leads to increase anti-inflammatorycytokine (concentration of IL-4). Variousmechanisms have been proposed for anti-inflammatory effect of captopril. Inprevious studies, it has been claimed that captopril is able to neutralize freeradicals due to the presence of thiol groups in its structure and perhaps oneof the anti-inflammatory mechanisms of this drug is the presence of thiolgroups in its structure and its ability to trapping free radicals which improve oxidative stress and inflammatory responses.The renin-angiotensinsystem (RAS) is known to play a major role in regulating electrolyte balanceand blood pressure.

More recently studies suggests that,the involvement of RAS in the inflammatory responses in the liver, kidney,cardiovascular system and lung (16). Ang II induced NF-?B activation and enhances the inflammatoryresponse by stimulating cytokine production (46). Captopril is ACE inhibitor.

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