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To evaluate the
possible protective effects of captopril against LPS-induced lung inflammation,
we measured the total and differential WBC, MDA, SOD, CAT, thiol levels and concentration
of IFN_?, PGE2, TGF-?1 and IL-4 in BALF. The LPS model is widely used and has
been shown to closely mimic the development of inflammation (21). The prolonged intraperitoneal LPS injection model are often used
to generate a systemic inflammatory response that comprises a more complicated
condition, with interactions between the whole body and the lung (22).

The result of
this study show increas MDA concentration, total WBC, percent of neutrophils, basophils
and macrophages, concentration of IFN_?, PGE2, TGF-?1, as well as decreased
percent of lymphocytes, total thiol groups, CAT and SOD activity in the BALF of
the LPS group. .All these changes support occurrence of systemic inflammation
and induction of an animal model of lung inflammation in rats.

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

According to
the results of the present study, oxidative stress was significant increased in
MDA and also decrease in total thiol groups and activity of catalase and
superoxide dismutase enzymes in BALF of LPS group compared to the control
group, which is similar to the results of previous studies (30, 31). Oxidative stress results from imbalance betwen
oxidant–antioxidant system with an increase of oxidants or a decrease of
antioxidants (31). In the pathogenesis of lung inflammation, Oxidative stress play
an important role, not only through direct injurious effects, but also by
involvement in the cellular and molecular mechanisms that control lung
inflammation (32). Reactive oxygen species (ROS), such as the hydroxyl radical (OH)
and the superoxide anion (O2) can cause damage and promote
inflammation. Against the damaging effects of O2, SOD is the primary
enzymatic 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 peroxidation
and its concentration has a positive correlation with reactive oxygen radicals (34). In the pathogenesis of
lung inflammation, peroxidation of polyunsaturated fatty acids due to the
effects on cell membrane function, inactivation of membrane-bound receptors and
enzymes, and increased tissue permeability (35). Thiol groups are important antioxidants in the body and reducing of
this antioxidants, leads to activation of NF-?B and increased transcription of
inflammatory genes (36).

The results of
this 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 control
group which is compatible with previous studies (37, 38) .

cytokines such as tumor necrosis factor-a (TNF-a) and  interleukins (IL)-1 are critical linkers
between the innate and adaptive cell-mediated immunity. They activate growth
and differentiation of T- and B-lymphocytes, and macrophages, and thus
inflammatory processes (39, 40). Interferon gamma is a pro-inflammatory cytokine that plays an
important role in providing antigens and activating T cells (41).  TGF-?1 is fibrogenic
cytokine  that play important role in pathogenesis
of lung inflammation and lung injury by various mechanisms, including
inhibiting activation and proliferation of immune cells, regulating
extracellular matrix, inducing apoptosis, inhibiting the production of
proteases, and stimulating the production of protease inhibitors. (42, 43). COX-2 is the
largest PGE-2 synthesizer (44). LPS is a potent activator of inflammatory
pathways with NF-?B activation. By activating NF-?B, the transcription of the
isoenzyme gene of  COX-2 were increases,
which increases the amount of PGE-2 (45). Our result show decrease in  concentration of
IL-4 in LPS group however in studies that have been acutely investigated by
LPS, the level of IL-4 has increased (11). IL-4  is anti-inflammatory
cytokine. At the beginning of the inflammation, the body tries to suppressing
inflammation process by increasing anti-inflammatory cytokines, but with
prolonged and chronic inflammation, the body’s activity were impaired, so reduced
anti-inflammatory cytokinesm1 .

Result of this study demonstrated the protective effect of captopril on
LPS-induced lung inflammation in rat. Captopril
suppressed LPS-induced lung inflammation in rat and reduced inflammatory
markers in the lung. Pretreatment and treatment with captopril in a dose dependent manner, significantly
reduced lung inflammation with decrease oxidative stress, total and percentage
of WBC and inflammatory cytokines. These results indicated that,
captopril reduced oxidative stress with decrease  MDA concentration and increase total thiol
groups and activity of SOD and CAT enzymes. On the other hand captopril reduced
concentration of inflammatory cytokines (concentration of IFN_?, PGE2 and TGF-?1)
and with improvement of inflammatory condition, leads to increase anti-inflammatory
cytokine (concentration of IL-4).

mechanisms have been proposed for anti-inflammatory effect of captopril. In
previous studies, it has been claimed that captopril is able to neutralize free
radicals due to the presence of thiol groups in its structure and perhaps one
of the anti-inflammatory mechanisms of this drug is the presence of thiol
groups in its structure and its ability to trapping free radicals which improve oxidative stress and inflammatory responses.

The renin-angiotensin
system (RAS) is known to play a major role in regulating electrolyte balance
and 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 inflammatory
response by stimulating cytokine production (46). Captopril is ACE inhibitor.

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