Paraquat-induced Lung Injury In Rats Research Articles

Evaluation of the protective effect of Curcuma longa and PPARγ agonist, pioglitazone on paraquat-induced lung injury in rats.

The inhalation of paraquat (PQ), one of the most widely used herbicides in the world, can result in lung injury. Curcuma longa (Cl) has long history in traditional and folk medicine for the treatment of a wide range of disorders including respiratory diseases. The aim of the present work was to evaluate the preventive effect of Cl on inhaled PQ-induced lung injury in rats. Male Wistar rats were divided into 8 groups (n = 7), one group exposed to saline (control) and other groups exposed to PQ aerosol. Saline (PQ), Cl extract, (two doses), curcumin (Cu), pioglitazone (Pio), and the combination of Cl-L + Pio and dexamethasone (Dex) were administered during the exposure period to PQ. Total and differential white blood cell (WBC) counts, oxidant and antioxidant indicators in the bronchoalveolar lavage (BALF), interleukin (IL)-10, and tumor necrosis alpha (TNF-α) levels in the lung tissues, lung histologic lesions score, and air way responsiveness to methacholine were evaluated. WBC counts (Total and differential), malondialdehyde level, tracheal responsiveness (TR), IL-10, TNF-α and histopathological changes of the lung were markedly elevated but total thiol content and the activities of catalase and superoxide dismutase were decreased in the BALF in the PQ group. Both doses of Cl, Cu, Pio, Cl-L + Pio, and Dex markedly improved all measured variables in comparison with the PQ group. CI, Pio, and Cl-L + Pio improved PQ-induced lung inflammation and oxidative damage comparable with the effects of Dex.

WITHDRAWN: Curcuma longa alone and in combination with pioglitazone attenuates paraquat-induced lung injury in rats through improving inflammation, oxidative stress and fibrosis

Background and aimThe therapeutic effects of pioglitazone (Pio), dexamethasone (Dexa) and Curcuma longa (Cl) on inhaled paraquat (PQ)-induced lung oxidative stress, inflammation, pathology changes and tracheal responsiveness were evaluated. Experimental procedureOne group of rats was exposed to saline (group C) and six groups to PQ aerosols. One group of PQ-exposed rats was given drinking water alone (group PQ), while other groups were received drinking water containing; two doses of Cl. (150 and 600 mg/kg, Cl-L and Cl–H), Pio (5 mg/kg), Pio + Cl-L and Daxa (0.03 mg/kg), (7 rat in each group). Results and conclusionIn PQ group, total and differential WBC counts, malondialdehyde (MDA) in the BALF, cytokine levels (INF-γ and IL-10), lung pathological changes and TR were remarkably increased but the BALF thiol, catalase (CAT) and superoxide dismutase (SOD) levels were reduced (for interstitial necrosis, p < 0.05 and for other cases, p < 0.001). Treatment of rats with Cl–H and Pio + Cl-L, significantly improved all measured variables, treatment with Pio and Cl-L improved most variables and treatment with Pio only few variables (p < 0.05 to p < 0.01). The improvements in almost all variables (except some pathological changes) in the Pio + Cl-L group were significantly higher than the Pio and Cl-L groups alone (p < 0.05 to p < 0.001).Curcuma longa ameliorated lung damage induced by inhaled PQ similar to dexamethasone and Pio and a synergic effect between Cl and Pio was observed, suggesting, amplified the activation effects of Pio on PPARs by Cl.

Evaluation of nano-curcumin against inhaled paraquat-induced lung injury in rats.

Acute lung injury (ALI) remains a significant source of morbidity and mortality in critically ill patients and currently there is no efficient therapy for this condition. The aim of this research was to evaluate the protective activity of nano-curcumin (nano-CU) as a natural anti-inflammatory and antioxidant agent, against inhaled paraquat (PQ)-induced lung injury. One group of rats was exposed to saline (control group, Ctrl) and six groups to PQ aerosol (54mg/m3 on alternate days 8 times, each time for 30min) treated with drinking water alone (group PQ), 2 and 8mg/kg nano-CU (nano + CU(L) and nano + CU(H)), 5mg/kg pioglitazone (PIO), nano-CU(L) + PIO or 0.03mg/kg dexamethasone (Dexa) for 16days after PQ exposure period. PIO and Dexa were intraperitoneal (ip) injected and nano-CU was administered orally (po), (6 rats in each group). In the PQ group, total and differential WBC counts, malondialdehyde (MDA) in the bronchoalveolar lavage fluid (BALF), interferon gamma (INF-γ) and interleukin 10 (IL-10) levels in the lung tissues, lung pathological changes, and tracheal responsiveness were increased but the BALF thiol, catalase (CAT) and superoxide dismutase (SOD) levels were reduced. In treated groups with nano-CU(H) and PIO + nano-CU(L), all measured variables, in Dexa and nano-CU(L) treated groups, most variables and in the PIO group only a few variables were improved. The improvement of most variables in the PIO + nano-CU(L) group was significantly higher than in the PIO and nano-CU(L) groups alone. Nano-CU ameliorated lung damage induced by inhaled PQ similar to dexa and a synergic effect between nano-CU and PIO was observed, suggesting, a possible PPAR-γ receptor-mediated effect of curcumin.

Effects of Nintedanib associated with Shenfu Injection on paraquat-induced lung injury in rats

Objective: To study the effects of Nintedanib associated with Shenfu Injection on lung injury induced by paraquat (PQ) intoxication. Methods: In September 2021, a total of 90 SD rats were divided into 5 groups in random, namely control group, PQ poisoning group, Shenfu Injection group, Nintedanib group and associated group, 18 rats in each group. Normal saline was given by gavage route to rats of control group, 20% PQ (80 mg/kg) was administered by gavage route to rats of other four groups. 6 hours after PQ gavage, Shenfu Injection group (12 ml/kg Shenfu Injection), Nintedanib group (60 mg/kg Nintedanib) and associated group (12 ml/kg Shenfu Injection and 60 mg/kg Nintedanib) were administered with medicine once a day. The levels of serum transforming growth factor beta1 (TGF-β1), interleukin-1 beta (IL-1β) were determined at 1, 3 and 7 d, respectively. The pathological changes of lung tissue, the ratio of wet weight and dry weight (W/D) of lung tissue, the levels of superoxide dismutase (SOD) and malondialdehyde (MDA) in lung tissue were observed and determined after 7 d. Western blot was used to analyse the expression levels of fibroblast growth factor receptor 1 (FGFR1), platelet derivation growth factor receptor alpha (PDGFRα), vascular endothelial growth factor receptor 2 (VEGFR2) in lung tissue after 7 d. Results: The levels of TGF-β1, IL-1β in all poisoning groups went up first and then went down. The levels of TGF-β1, IL-1β in associated group at 1, 3, 7 d were lower than that of PQ poisoning group, Shenfu Injection group and Nintedanib group at the same point (P<0.05). Pathological changes of lung tissue under the light microscopes showed that the degrees of hemorrhage, effusion and infiltration of inflammatory cells inside the alveolar space of Shenfu Injection group, Nintedanib group and associated group were milder than that of PQ poisoning group, and the midest in associated group. Compared with control group, the W/D of lung tissue was higher, the level of MDA in lung tissue was higher, while the level of SOD was lower, the expressions of FGFR1, PDGFRα and VEGFR2 in lung tissue were higher in PQ poisoning group (P<0.05). Compared with PQ poisoning group, Shenfu Injection group and Nintedanib group, the W/D of lung tissue was lower, the level of MDA in lung tissue was lower, while the level of SOD was higher, the expressions of FGFR1, PDGFRα and VEGFR2 in lung tissue were lower in associated group (P<0.05) . Conclusion: Nintedanib associated with Shenfu Injection can relieve lung injury of rats induced by PQ, which may be related to Nintedanib associated with Shenfu Injection can inhibit the activation of TGF-β1 and the expressions of FGFR1, PDGFRα, VEGFR2 in lung tissue of rats.

Aqueous Thunbergia laurifolia leaf extract alleviates paraquat-induced lung injury in rats by inhibiting oxidative stress and inflammation

BackgroundParaquat (PQ) has been reported to have a high mortality rate. The major target organ of PQ poisoning is the lungs. The pathogenesis of PQ-induced lung injury involves oxidative stress and inflammation. Unfortunately, there is still no effective antidote for PQ poisoning. We hypothesized that aqueous Thunbergia laurifolia (TL) leaf extract is a possible antidote for PQ-induced lung injury.MethodsThe total phenolic content and caffeic acid content of an aqueous extract of TL leaves were analyzed. Male Wistar rats were randomly divided into four groups (n = 4 per group): the control group (administered normal saline), the PQ group (administered 18 mg/kg body weight (BW) PQ dichloride subcutaneously), the PQ + TL-low-dose (LD) group (administered PQ dichloride subcutaneously and 100 mg/kg BW aqueous TL leaf extract by oral gavage) and the PQ + TL-high-dose (HD) group (administered PQ dichloride subcutaneously and 200 mg/kg BW aqueous TL leaf extract by oral gavage). Malondialdehyde (MDA) levels and lung histopathology were analyzed. In addition, the mRNA expression of NADPH oxidase (NOX), interleukin 1 beta (IL-1β), and tumor necrosis factor alpha (TNF-α) was assessed using reverse transcription-polymerase chain reaction (RT-PCR), and the protein expression of IL-1β and TNF-α was analyzed using immunohistochemistry.ResultsThe total phenolic content of the extract was 20.1 ± 0.39 μg gallic acid equivalents (Eq)/mg extract, and the caffeic acid content was 0.31 ± 0.01 μg/mg. The PQ group showed significantly higher MDA levels and NOX, IL-1β and TNF-α mRNA expression than the control group. Significant pathological changes, including alveolar edema, diffuse alveolar collapse, hemorrhage, leukocyte infiltration, alveolar septal thickening and vascular congestion, were observed in the PQ group compared with the control group. However, the aqueous TL leaf extract significantly attenuated the PQ-induced increases in MDA levels and NOX, IL-1β and TNF-α expressions. Moreover, the aqueous TL leaf extract ameliorated PQ-induced lung pathology.ConclusionThis study indicates that aqueous TL leaf extract can ameliorate PQ-induced lung pathology by modulating oxidative stress through inhibition of NOX and by regulating inflammation through inhibition of IL-1β and TNF-α expressions. We suggest that aqueous TL leaf extract can be used as an antidote for PQ-induced lung injury.

Retraction Note: Carvacrol and PPAR\u03b3 agonist, pioglitazone, affects inhaled paraquat-induced lung injury in rats

Retraction Note: Carvacrol and PPAR\u03b3 agonist, pioglitazone, affects inhaled paraquat-induced lung injury in rats

RETRACTED ARTICLE: Carvacrol and PPAR\u03b3 agonist, pioglitazone, affects inhaled paraquat-induced lung injury in rats

Exposed rats to normal saline and paraquat (PQ) aerosol as control and PQ group, rats exposed to PQ and treated with 20 and 80 mg/kg/day carvacrol, 5 and 10 mg/kg/day pioglitazone, low dose of pioglitazone + carvacrol and 0.03 mg/kg/day dexamethasone (Dexa) for 16 days after the end of PQ exposure were studied (n = 6 in each group). Lung pathological changes, tracheal responsiveness to methacholine and ovalbumin (OVA) as well as transforming growth factor beta (TGF-β) and interleukin (IL)-6 level in the lung tissue homogenize as well as TGF-β, IL-6, oxidant and antioxidant levels oxidant and antioxidants were increased in PQ group (p < 0.01 to p < 0.001). Lung pathological changes, tracheal responsiveness to methacholine and OVA as well as TGF-β, IL-6 oxidant and antioxidant levels were improved in all treated groups except lung pathological changes in treated group with low dose of pioglitazone (p < 0.05 to p < 0.001). The effects of low dose of pioglitazone and carvacrol alone were significantly lower than in the combination group of low dose of pioglitazone + carvacrol (p < 0.05 to p < 0.001). Carvacrol treatment improved inhaled PQ-induced lug injury similar to the effects of dexamethasone. The synergic effect of carvacrol and pioglitazone suggests PPAR-γ receptor mediated effects of carvacrol on inhaled PQ-induced lung injury.

Procyanidin B2 protects rats from paraquat-induced acute lung injury by inhibiting NLRP3 inflammasome activation

Paraquat is a commonly used heterocyclic herbicide and has high toxicity by causing acute lung injury. There is no effective treatment for paraquat poisoning. We evaluated the effects of procyanidin B2, a natural dietary phytochemical, on paraquat-induced lung injury in rats. Paraquat was used to induce acute lung injury of rats, which were administered with procyanidin B2. The lung injury was evaluated by measuring the lung/body weight ratio, the histology and PMNs count. The oxidative stress was assessed by detecting ROS-mediated indices in the BALF. The expression of IL-1β and IL-18 were detected by RT-PCR and ELISA. The levels of NLRP3 inflammasome components including NLRP3, ASC and caspase-1 were detected by western blot. The lung injury in the paraquat-induced models in NLRP3 gene silenced animals was compared with the same lung injury model treated with procyanidin B2. Administration of procyanidin B2 significantly reduced paraquat-induced lung injury with lower BALF PMNs count, MPO activity, MDA level and elevated SOD activity. Procyanidin B2 suppressed expression of IL-1β and IL-18 at both RNA and protein levels, similar to the NLRP3 gene silenced rats. Compared to paraquat-induced group, procyanidin B2 showed remarkably decreased NLRP3, ASC and caspase-1 signals in the lung tissues in a dose-dependent manner. Procyanidin B2 significantly suppressed the activation of NLRP3 inflammasome in the lung tissue induced by paraquat in the rat model. This finding revealed a novel mechanism by which procyanidin B2 exerts anti-inflammatory effects and their clinical benefits in health.

The effect of captopril and losartan on paraquat-induced pulmonary fibrosis and PlGF expression in the lungs of rats

Objective: To investigate the dynamic expression of placenta growth factor (PlGF) in the lungs and its role in paraquat-induced pulmonary fibrosis and to evaluate the effect of ACEI captopril and AT (1) -receptor blocker losartan on paraquat-induced pulmonary fibrosis. Methods: 84 adult healthy female Sprague-Dawley (SD) rats were randomly divided into four groups of different treatments designated as: Control, PQ alone (PQ) , captopril treatment, losartan treatment. Each group was divided into three subgroups of seven animals each. The animals were killed at either 7, 14 or 28 days after PQ administration. The rats in PQ group, treatment group were treated intragastrically (ig) with PQ (40 mg/kg) and the rats in control group were treated with the same dose of saline at the beginning of the experiment. The treatment group received Captopril (60 mg/kg; ig) or Losartan (10 mg/kg; ig) once a day respectively after PQ administration and the other two groups received saline. At the given timepoint, animals were sacrificed and lungs were harvested. A semiquantitative assay of histological examination, hydroxyproline in lung tissues were used to determine the severity of alveolitis and fibrosis. RT-PCR and immunohistochemistry were used to detect the mRNA and protein expression of PlGF. Results: Inflammatory cell infiltration and fibrotic scores were more prominent in the model group, hydroxyproline contents in lung tissue were significantly increased after PQ administration compared to the control group. Captopril, losartan apparently attenuated the degree of lung injury and pulmonary fibrosis. On 7th, 14th days, the levels of alveolitis in the intervention groups were significantly alleviated as compared with the model group (P<0.05) . On 28th days, the levels of pulmonary fibrosis in the intervention groups were significantly alleviated as compared with model group (P<0.05) . The hydroxyproline contents in the intervention groups were significantly decreased as compared with model group (P<0.01) . PlGF mRNA on day 7, 14, 28 (1.28±0.29vs0.10±0.01、0.80±0.07vs0.10±0.01、0.65±0.13vs0.10±0.01) in the PQ group were all upregulated as compared with that of the control group. PlGF mRNA on day 7, 14, 28 in the captopril and Losartan intervention groups were significantly decreased (0.94±0.04、0.71±0.09、0.52±0.24 and 0.80±0.12、0.66±0.11、0.51±0.03) . PlGF positive expression index on day 7, 14, 28 (2.27±0.34 vs0.13±0.01、1.78±0.41 vs0.14±0.03、1.25±0.69 vs0.13±0.01) in the PQ group were all upregulated as compared with that of the control group. PlGF positive expression index on day 7, 14, 28 in the captopril and Losartan treatment groups were significantly decreased (1.53±0.78、1.17±0.79、0.97±0.61 and 1.36±0.63、1.24±0.80、0.83±0.47) . PlGF positive expression index on day 7 in the two intervention groups were significantly decreased, as compared with PQ group (P<0.05) . Conclusion: PlGF may plays an important role in the development of pulmonary fibrosis following paraquat-induced lung injury in rats. Captopril and losartan had an inhibitory effect on paraquat-induced pulmonary fibrosis, and the effect may be due to inhibition of angiotensin II and, in part, be associated with reduction in PlGF.

The role of p38 MAPK in acute paraquat-induced lung injury in rats

Context: Paraquat (PQ; 1,1'-dimethyl-4,4'-bipyridinium dichloride) is highly toxic and accounts for a large proportion of the herbicide poisonings seen in clinic. The major cause of mortality is respiratory failure. The p38 mitogen-activated protein kinase (MAPK) signal transduction pathway coordinates various cellular stress responses that have been shown to participate in the pathogenesis of PQ-induced lung injury.Objective: To evaluate the effect of the specific p38 MAPK inhibitor SB203580 on PQ-induced lung injury and cytokine secretion.Methods: In groups of 24, rats were treated with PQ, PQ and SB203580 (SB + PQ), SB203580 alone (SB) or normal saline (control group). Six rats from each group were euthanized at 1, 3, 5 or 7 d. Pathology of lung specimens was scored through hematoxylin and eosin staining. Edema in the lung was quantified from wet-to-dry weight ratios. p38 and p-p38MAPK proteins were measured via electrochemiluminescent Western blots. tumor necrosis factor (TNF)-alpha and interleukin-1 beta (IL-1β) concentrations in lung specimens and bronchoalveolar lavage fluid (BALF) were quantified via enzyme-linked immunosorbent assay.Results: The mortality rate of the SB + PQ group (16.7%) was significantly lower than that of the PQ group (33.3%; p < 0.05). The PQ group had significantly higher pulmonary histology scores, wet-to-dry weight ratios and phosphorylated p-p38 MAPK levels, as well as higher IL-1β and TNF-alpha levels in BALF and lung tissues, that did the SB + PQ and control groups (p < 0.05, all).Conclusion: The data suggest that the p38 MAPK signaling pathway has an important role in regulating the production of IL-1β and TNF-alpha in PQ-induced lung injury in rats.

Ozone therapy ameliorates paraquat-induced lung injury in rats.

Paraquat (PQ) overdose can cause acute lung injury and death. Ozone therapy (OT) was previously demonstrated to alleviate inflammation and necrosis in various pathologies. We therefore hypothesized that OT has ameliorative and preventive effects on PQ-induced lung damage due to anti-inflammatory and antioxidants properties. Sprague-Dawley rats (n = 24) were separated into three groups: sham, PQ, and PQ+OT groups. 15 mg/kg PQ was administered intraperitoneally in PQ and PQ+OT groups to induce experimental lung injury. One hour after PQ treatment, PQ+OT group was administered a single dose of ozone-oxygen mixture (1 mg/kg/day) by intraperitoneal route for four consecutive days. The animals were sacrificed on fifth day after PQ administration. Blood samples and lung tissues were collected to evaluate the inflammatory processes, antioxidant defense and pulmonary damage. Serum lactate dehydrogenase (LDH) and neopterin levels, tissue oxidative stress parameters, total TGF-β1 levels, and histological injury scores in PQ+OT group were significantly lower than PQ group (P<0.05, PQ vs. PQ+OT). Total antioxidant capacity in PQ+OT group was significantly higher than PQ group (P < 0.05, PQ+OT vs. PQ). These findings suggest that outcome in PQ-induced lung injury may be improved by using OT as an adjuvant therapy.

Mifepristone-inducible recombinant adenovirus attenuates paraquat-induced lung injury in rats.

To investigate the effects of overexpression of nuclear factor E2-related factor-2 (NRF2) on lung injury in rats exposed to paraquat (PQ) poisoning. A mifepristone (RU486)-inducible recombinant adenoviral vector carrying the human NRF2 gene (Ad-RUNRF2) was constructed and transfected via airway into the rats 7 days before the administration of RU486. Rats were orally challenged with PQ at 20 mg/kg 24 h after the injection of RU486. On days 0.5, 3 and 21 after PQ poisoning, the expressions of NRF2 and cytokines related to inflammation and oxidation in lung tissue were examined. RU486 remarkably enhanced NRF2 mRNA and NRF2 protein levels in Ad-RUNRF2-transfected rats in a dose-dependent manner (p < 0.01). PQ stimulated compensatory overexpression of NRF2, heme oxygenase 1 (HO-1) and NAD(P)H quinone oxidoreductase 1 (NQO-1) in lungs on days 0.5 and 3 after exposure (p < 0.05), but depleted the expression of catalase (CAT), glutathione peroxidase (GSH-Px) and glutathione (GSH), with an increased malondialdehyde (MDA) (p < 0.05). However, pretreatment with Ad-RUNRF2 and RU486 strongly enhanced the expression levels of NRF2, HO-1, NQO-1, CAT and GSH-Px in the lungs of PQ intoxicated rats, with increased GSH and decreased MDA (p < 0.05). Pretreatment with Ad-RUNRF2 and RU486 also strongly suppressed the PQ-induced activation of nuclear factor κB (NF-κB) and decreased the levels of tumour necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6). In addition, Ad-RUNRF2 and RU486 induction significantly reduced PQ-induced pathological changes in lungs and attenuated lung oedema and protein leakage caused by PQ (p < 0.05). RU486-induced overexpression of NRF2 in lungs transfected with Ad-RUNRF2 can ameliorate PQ-induced lung injury by the activation of the NRF2-antioxidant response element (ARE) pathway.

Protective effect and mechanisms of pituitrin on acute paraquat-induced lung injury in rats

To explore the protective effect of pituitrin on the development of paraquat-induced lung injury in rats. Sixty healthy Sprague Dawley female rats were randomized into 3 groups of control, paraquat and treatment (80 mg/kg, intragastric) groups (n = 20 each) Each group was divided into 4, 6, 12 and 24 h subgroups (n = 5 each). The treatment group received pituitrin, injection via internal jugular vein 30 minutes after paraquat dosing. As controls, control and paraquat groups were injected with an equal volume of saline. The paraquat content in serum and lung tissue was measured by high-performance liquid chromatography-mass spectrometry (HPLC-MS). And the levels of tumor necrosis factor-alpha (TNF-α) in sera and nuclear factor-kappa B (NF-κB) in lung tissue and the content of protein in bronchoalveolar lavage (BAL) fluid were detected at various timepoints. Lung wet-to-dry weight ratio (W/D) was recorded after pituitrin dosing. In addition, pathological changes were also observed. The highest drug concentration of paraquat in lung tissue was far lower in the treatment group than that in the paraquat group ((7.67 ± 0.91) vs (13.27 ± 0.95) µg/g, P = 0.002). There were the same result in sera ((1 695 ± 274) vs (5 377 ± 576) ng/ml, P = 0.003). The area under the concentration-time curve in the treatment group was significantly lower than that in the paraquat group (10 482 vs 43 441, P = 0.000). The levels of NF-κB in lung tissue and TNF-α in sera in the treatment group were lower than those in the paraquat group (TNF-α: 24 h: (1.85 ± 0.22) vs (2.59 ± 0.13) ng/ml, P = 0.020; NF-κB: 24 h: (88.0 ± 2.7) vs (101.8 ± 2.8) ng/g, P = 0.003). And there was a decrease in the content of protein in BAL fluid in the treatment group versus the paraquat group (BALF protein: 24 h: (125.9 ± 4.2) vs (192.7 ± 6.5)µg/ml, P = 0.003), lung W/D significantly decreased in the treatment group versus the paraquat group (12 h: 3.50 ± 0.14 vs 3.73 ± 0.15, P = 0.043; 24 h: 3.41 ± 0.06 vs 3.61 ± 0.09, P = 0.047). In addition, when compared with the paraquat group, the pituitrin-treated rats showed a mitigation of inflammatory response in lungs and reduced pulmonary edema. Pituitrin treatment decreases the content of paraquat in sera and lung homogenate in intoxicated rats and alleviates lung injury so that it may become a useful adjuvant in the treatment of acute lung injury.

Protective effect of quercetin against paraquat-induced lung injury in rats

Aims Paraquat (PQ) is known to induce pulmonary injury via a redox cyclic reaction. The present study was aimed to determine the protective effects of quercetin against PQ-induced pulmonary injury in association with its antioxidant activity. Main methods Male rats were challenged acutely by PQ (50 mg/kg, i.p.) with or without quercetin post-treatment. Pulmonary heme oxygenase-1 (HO-1) expression, malondialdehyde (MDA) level, and the total oxyradical scavenging capacity (TOSC) toward hydroxyl, peroxyl radicals and peroxynitrite were measured 24 h after PQ treatment. Different groups of rats were instilled with PQ (0.5 mg/kg) directly into the right lung. Quercetin was administered to the rats daily for 14 days after PQ instillation. Serum NO, pulmonary glutathione (GSH) and 4-hydroxyproline (4-HP) concentrations were quantified in conjunction with histopathological examination to determine the fibrotic changes in lung. Key findings Pulmonary MDA level and HO-1 expression were elevated and the TOSC was reduced rapidly by an intraperitoneal dose of PQ. These changes were inhibited by quercetin post-treatment. In rat lungs instilled with PQ 14 days before, NO, MDA and 4-HP were elevated, and GSH was reduced, which were all inhibited significantly by daily quercetin treatment. Histopathological examination also revealed that quercetin ameliorated the increase in fibroblast distribution and collagen deposition in the lungs instilled with PQ. Significance The present results demonstrate that quercetin administration to rats effectively inhibits the development of PQ-induced pulmonary injury most probably via its antioxidant activity.

Inhaled nitric oxide improves the survival of the paraquat-injured rats

The purpose of this study was to evaluate the effects of inhaled nitric oxide (NO) on the paraquat-induced lung injury in rats. The rats were assigned to four groups: control; inhaled NO (5 ppm); paraquat (PQ, 30 mg/kg); and PQ+NO group. For first 18 h the inhalation of NO mixed with room air was performed. Total white blood cell (WBC), neutrophil, total protein, lactate dehydrogenase (LDH), transforming growth factor-β1 (TGF-β1) in serum and/or bronchoalveolar lavage (BAL) fluid, serum malonaldehyde (MDA), and myeloperoxidase (MPO) of lung were measured and lung histopathology were also reviewed. The 72-h survival rate of PQ group was 58%, but the survival rate of PQ+NO group, NO group and control group were 100%, respectively. The serum MDA and TGF-β1 in BAL fluid and blood of PQ+NO group were significantly lower than those of PQ group. However, inhaled NO did not decrease the elevated total WBC and neutrophil counts, and total protein, LDH and MPO activity in the lung injured by PQ. The alveolar septal thickening and inflammatory cell infiltration were not different between PQ and PQ+NO groups. NO inhalation may be beneficial for the survival of paraquat-induced injured rats by attenuating lipid peroxidation and production of TGF-β1.

Airspace configuration at different transpulmonary pressures in normal and paraquat-induced lung injury in rats.

The aim of this study is to evaluate histoarchitecture of airspaces at different positive transpulmonary pressures, both during inflation and deflation of excised normal and paraquat-damaged rat lungs. Freshly excised lungs were placed in a plethysmograph connected to a graded pipette. Immediately after the achievement of the desired pressure level (5, 15, 25 cm H2O during inflation, and 15 and 5 cm H2O during deflation), the tracheal cannula was occluded and lungs were quick-frozen by immersion in liquid nitrogen, and fixed using Carnoy's solution. Sections representing the central and peripheral areas of the lungs were sampled and processed for paraffin embedding and stained with hematoxylin-eosin. By means of stereological techniques, surface-to-volume ratio (S/V) and the fraction of large-volume gas-exchanging airspaces (LVGEAS) were determined. We observed in paraquat-treated animals evidence of alveolar instability close to the resting volume. Structural unevenness was minimized by massive recruitment followed by alveolar pressurization. In conclusion, this work demonstrates that morphological evidence of uneven distribution of inspired air may be partially reversed by applying larger alveolar pressures. These larger pressures applied at the end-expiration in vivo (positive end-expiratory pressure, PEEP) can minimize the distortion of lung microarchitecture during ventilation.

Correlation between lipid peroxidation and morphological manifestation of paraquat-induced lung injury in rats

Biochemical and morphological studies of rat lung were performed to determine the role of lipid peroxidation in the in vivo lung toxicity of paraquat. Two injections of 20 mg/kg paraquate were administered intraperitoneally every other day. While notable epithelial damage in the lungs was observed on the day after the second paraquat injection and progressed through the 5th day, the concentration of lipid peroxides in the rat lungs did not increase by the 3rd day after the injection. The lipid peroxide concentrations increased after the 5th day post-injection, and reached the maximum concentrations on the 7th day, when the damaged alveolar surface had been mostly repaired by regenerative pneumocytes. On the other hand, the delayed increase of lung lipid peroxides in paraquat-treated rats paralleled the increased number of macrophages in the lung, which reached maximum numbers on the 7th day. Glutathione peroxidase activity in the lungs also increased with a similar time course. Macrophages from the lungs contained a large amount of engulfed degradation products and cellular debris, and immunohistochemical study showed high glutathione peroxidase content on the 5th and 7th days. These results suggest that lipid peroxidation is a relatively late event in the in vivo paraquat-treated lung and that the delayed increase of lipid peroxides in the lungs occurs from the phagocytic activities of macrophages rather than from toxic cell injury.

Role of alveolar macrophages in development of paraquat-induced lung injury

It is not known if alveolar macrophages (AM) play an important role in the development of interstitial changes in the lung. The purpose of the present study was to learn if AM are related to the initiation of paraquat-induced lung injury in rats. An intraperitoneal injection of 10 mg/kg paraquat was followed by a rapid increase in the number of viable AM. This effect reached a maximum at 24 h after injection. When 90 mg/kg of methylprednisolone was injected subcutaneously at the same time of the administration of paraquat there was no increase in the number of viable AM. After weekly injection of 5 mg/kg paraquat for six weeks, there were histological changes which were significantly supressed by the simultaneous administration of methylprednisolone. Methylprednisolone, however, did not show such suppressive effects when administered 4 d after the injection of paraquat. It is suggested that the emergence of viable AM is one of the key phenomena in the initiation of interstitial changes in paraquat-induced lung injury.