BACKGROUNDOrganophosphate poisoning is an important health problem in developing countries which causes death mainly by inducing acute lung injury. In this study, we examined the effects of penehyclidine hydrochloride (PHC), a selective M-receptor inhibitor, on dichlorvos-induced acute lung injury in swine.

METHODSTwenty-two female swines were randomly divided into control (n = 5), dichlorvos (n = 6), atropine (n = 6), and PHC (n = 5) groups. Hemodynamic data, extravascular lung water index (EVLWI), and pulmonary vascular permeability index (PVPI) were monitored; blood gas analysis and acetylcholinesterase (AchE) levels were measured. PaO2/FiO2, cardiac index (CI), and pulmonary vascular resistance indices (PVRI) were calculated. At termination of the study, pulmonary tissue was collected for ATPase activity determination and wet to dry weight ratio (W/D) testing 6 hours post-poisoning. TUNEL assay, and Bax, Bcl-2, and caspase-3 expression were applied to pulmonary tissue, and histopathology was observed.

RESULTSAfter poisoning, PHC markedly decreased PVRI, increased CI more effectively than atropine. Anticholinergic treatment reduced W/D, apoptosis index (AI), and mitigated injury to the structure of lung; however, PHC reduced AI and caspase-3 expression and improved Bcl-2/Bax more effectively than atropine. Atropine and PHC improved ATPase activities; a significant difference between groups was observed in Ca(2+)-ATPase activity, but not Na(+)-K(+)-ATPase activity.

CONCLUSIONSThe PHC group showed mild impairment in pathology, less apoptotic cells, and little impact on cardiac function compared with the atropine group in dichlorvos-induced acute lung injury.

Acute Lung Injury ; chemically induced ; drug therapy ; Animals ; Dichlorvos ; toxicity ; Female ; Quinuclidines ; therapeutic use ; Swine

BACKGROUNDAn inflammatory response leading to organ dysfunction and failure continues to be a major problem after injury in many clinical conditions such as sepsis, severe burns, and trauma. It is increasingly recognized that atrial natriuretic peptide (ANP) possesses a broad range of biological activities, including effects on endothelial function and inflammation. A recent study has revealed that ANP exerts anti-inflammatory effects. In this study we tested the effects of human ANP (hANP) on lung injury in a model of oleic acid (OA)-induced acute lung injury (ALI) in rats.

METHODSRats were randomly assigned to three groups (n = 6 in each group). Rats in the control group received a 0.9% solution of NaCl (1 ml × kg(-1) × h(-1)) by continuous intravenous infusion, after 30 minutes a 0.9% solution of NaCl (1 ml/kg) was injected intravenously, and then the 0.9% NaCl infusion was restarted. Rats in the ALI group received a 0.9% NaCl solution (1 ml × kg(-1) × h(-1)) intravenous infusion, after 30 minutes OA was injected intravenously (0.1 ml/kg), and then the 0.9% NaCl infusion was restarted. Rats in the hANP-treated ALI group received a hANP (0.1 µg × kg(-1) × min(-1)) infusion, after 30 minutes OA was injected intravenously (0.1 ml/kg), and then the hANP infusion was restarted. The anti-inflammation effects of hANP were evaluated by histological examination and determination of serum cytokine levels.

RESULTSSerum interleukin (IL)-1β, IL-6, IL-10 and tumor necrosis factor (TNF) α were increased in the ALI group at six hours. The levels of all factors were significantly lower in the hANP treated rats (P < 0.005). Similarly, levels of IL-1β, IL-6, IL-10 and TNF-α were higher in the lung tissue in the ALI group at six hours. hANP treatment significantly reduced the levels of these factors in the lungs (P < 0.005). Histological examination revealed marked reduction in interstitial congestion, edema, and inflammation.

CONCLUSIONhANP can attenuate inflammation in an OA-induced lung injury in rat model.

Acute Lung Injury ; chemically induced ; drug therapy ; Animals ; Atrial Natriuretic Factor ; therapeutic use ; Disease Models, Animal ; Inflammation ; chemically induced ; drug therapy ; Male ; Oleic Acid ; toxicity ; Rats ; Rats, Wistar

Acute Lung Injury ; chemically induced ; drug therapy ; Animals ; Endotoxins ; Glycoproteins ; therapeutic use ; Male ; Propofol ; therapeutic use ; Rats ; Rats, Sprague-Dawley

ObjectiveExposure to halogens, such as chlorine or bromine, results in environmental and occupational hazard to the lung and other organs. Chlorine is highly toxic by inhalation, leading to dyspnea, hypoxemia, airway obstruction, pneumonitis, pulmonary edema, and acute respiratory distress syndrome (ARDS). Although bromine is less reactive and oxidative than chlorine, inhalation also results in bronchospasm, airway hyperresponsiveness, ARDS, and even death. Both halogens have been shown to damage the systemic circulation and result in cardiac injury as well. There is no specific antidote for these injuries since the mechanisms are largely unknown.

Data SourcesThis review was based on articles published in PubMed databases up to January, 2018, with the following keywords: "chlorine," "bromine," "lung injury," and "ARDS."

Study SelectionThe original articles and reviews including the topics were the primary references.

ResultsBased on animal studies, it is found that inhaled chlorine will form chlorine-derived oxidative products that mediate postexposure toxicity; thus, potential treatments will target the oxidative stress and inflammation induced by chlorine. Antioxidants, cAMP-elevating agents, anti-inflammatory agents, nitric oxide-modulating agents, and high-molecular-weight hyaluronan have shown promising effects in treating acute chlorine injury. Elevated free heme level is involved in acute lung injury caused by bromine inhalation. Hemopexin, a heme-scavenging protein, when administered postexposure, decreases lung injury and improves survival.

ConclusionsAt present, there is an urgent need for additional research to develop specific therapies that target the basic mechanisms by which halogens damage the lungs and systemic organs.

Acute Lung Injury ; chemically induced ; Animals ; Chlorine ; toxicity ; Halogens ; toxicity ; Humans ; Lung ; drug effects ; pathology ; Respiratory Distress Syndrome, Adult ; drug therapy

OBJECTIVETo observe the best dose of methylprednisolone improving lung injury in swine with paraquat intoxication.

METHODSAcute lung injury (ALI/ARDS) model was made by an intraperitoneal injection of a large dose of 20%PQ solution20 millilitres in swine. Then 24 swine were randomly divided into 4 groups: exposed PQ control group, 5 mg/kg of methylprednisolone group, 15 mg/kg of methylprednisolone group, 30 mg/kg of methylprednisolone group. All groups were based on the conventional rehydration for intervention, Arterial blood samples were collected before modeling and 0, 12, 24, 36 hours after different processing for blood gas analysis. At the same time heart rate (HR), mean arterial pressure (MAP), extravascular lung water index (EVLWI) and pulmonary vascular permeability index (PVPI) were measured by using PICCO (pulse indicator continuous cardiac output), lung tissue was obtained by punctureneedle to produce lung biopsy, then observe the pathological changes of lung tissue in the microscope.

RESULTS1. Comparison between groups: there is no significant difference about extravascular lung water index (EVLWI) and semi-quantitative score of lung tissue pathology in four groups (P > 0.05) before modeling, so is t0, there is significant difference at about extravascular lung water index and semi-quantitative score of lung tissue pathology 12 h, 24 h and 36 h after different processing (P < 0.05). Within the group: EVLWI and semi-quantitative score of Lung tissue pathology in four groups significantly increased when the model was made (P < 0.05), after different processing, EVLWI and semi-quantitative score of Lung tissue pathology in exposed PQ control group kept going up, in other three groups, EVLWI and semi-quantitative score of lung tissue pathology went down first and then went up, there is significant difference compared with t0 (P < 0.05). 2. Comparison between groups: there is no significant difference about oxygenation index in four groups (P > 0.05) before modeling, so is t0, there is significant difference about oxygenation at 12 h, 24 h and 36 h after different processing (P < 0.05). Within the group: oxygenation index in four groups significantly decreased when the model was made (P < 0.05), after different processing, oxygenation index in exposed PQ control group kept going down, in other three groups, it showed a downward trend after the first rise, there is significant difference compared with t0 (P < 0.05). 3. After medication for 36h, correlation analysis showed that EVLWI were negatively associated with oxygenation index (r = -0.427, P = 0.022) and positively associated with semi-quantitative score of Lung tissue pathology (r = 0.903, P = 0.034).

CONCLUSIONMethylprednisolone can obviously relieve lung injury caused by paraquat poisoning and improve oxygenation. After the model was made, within 24 hours, 30 mg/kg of methylprednisolone have advantage for the PQ poisoning swine, but 15mg/kg of methylprednisolone is best for improving lung injury induced by paraquat intoxication within 24 hours to 36 hours.

Acute Lung Injury ; chemically induced ; drug therapy ; Animals ; Blood Gas Analysis ; Capillary Permeability ; Extravascular Lung Water ; Heart Rate ; Lung ; Lung Injury ; Methylprednisolone ; administration & dosage ; therapeutic use ; Paraquat ; toxicity ; Swine

OBJECTIVETo investigate the effect of L-Arginine (L-Arg) on pulmonary surfactant (PS) expression and alveolar macrophage (AM) in rats with pulmonary injury induced by lipopolysaccharide (LPS).

METHODSModel of acute lung injury (ALI) was made by injection (iv) with LPS 5 mg/kg in rats. Fourty-eight male SD rats were randomly divided into 3 groups(n = 16): control, model (LPS) and L-Arg groups. L-Arg (500 mg/kg ip ,L-Arg group) or saline (control and LPS group) was administrated at 3 h or 6 h after LPS injection respectively for 3 h. The expression of surfactant protein A (SP-A) mRNA in the lung tissue was detected by ISH. The total protein (TP) in the bronchoalveolar lavage fluid (BALF) was detected. Rat AM were isolated from the bronchial alveolar lavage fluid of SD rats and harvested by selective plating technique. LPS and L-Arg were added to the culture medium. The concentration of nitric oxide (NO),the activity of lactate dehydrogenase (LDH), the contents of tumor necrosis factor alpha (TNF-alpha) and interleukin- 6 (IL-6) in the culture supernatants were respectively measured.

RESULTSCompared with the control group, the expression of SP-A mRNA was significantly decreased, the TP concentration was significantly increased in LPS group. Compared with LPS group at the same time points, treatment with L-Arg at 3 h after LPS, the expression of SP-A mRNA in lung tissue was increased markedly, whereas TP concentration was decreased significantly. In cultured rat AM, LDH activity, NO, TNF-alpha and IL-6 contents in culture medium were significantly increased in LPS group to compared with those of control group. LDH activity, TNF-alpha and IL-6 contents were decreased in L-Arg group compared with those of LPS group.

CONCLUSIONL-Arg can protect the lung against LPS-induced pulmonary injury by up-regulating the expression of PS and inhibiting inflammatory transmitters from AM.

Acute Lung Injury ; chemically induced ; drug therapy ; metabolism ; Animals ; Arginine ; pharmacology ; therapeutic use ; Lipopolysaccharides ; adverse effects ; Macrophages, Alveolar ; metabolism ; Male ; Pulmonary Surfactants ; metabolism ; Rats ; Rats, Sprague-Dawley

BACKGROUNDPediatric patients are susceptible to lung injury. Acute lung injury in children often results in high mortality. Partial liquid ventilation (PLV) has been shown to markedly improve oxygenation and reduce histologic evidence of injury in a number of lung injury models. This study was designed to examine the hypothesis that PLV would attenuate the production of local and systemic tumor necrosis factor (TNF)-α in an immature piglet model of acute lung injury induced by oleic acid (OA).

METHODSTwelve Chinese immature piglets were induced acute lung injury by OA. The animals were randomly assigned to two groups of six animals, (1) conventional mechanical ventilation (MV) group and (2) PLV with 10 ml/kg FC-77 group.

RESULTSCompared with MV group, the PLV group had better cardiopulmonary variables (P < 0.05). These variables included heart rate, mean blood pressure, blood pH, partial pressure of arterial oxygen (PaO2), PaO2/inspired O2 fraction (FiO2) and partial pressure of arterial carbon dioxide (PaCO2). PLV reduced TNF-α levels both in plasma and tissue compared with MV group (P < 0.05).

CONCLUSIONPLV provides protective effects against TNF-α response in OA-induced acute lung injury in immature piglets.

Acute Lung Injury ; chemically induced ; metabolism ; therapy ; Animals ; Animals, Newborn ; Liquid Ventilation ; methods ; Oleic Acid ; toxicity ; Swine ; Tumor Necrosis Factor-alpha ; blood ; metabolism

OBJECTIVETo observe the therapeutic effect and mechanism of penehyclidine hydrochloride on paraquat-induced acute lung injury.

METHODS80 healthy adult male Wistar rats were randomly assigned into control groups (10 rats), 100 mg/kg PQ group (10 rats), 100 mg/kg PQ plus 33 µg/kg penehyclidine hydrochloride treatment group (30 rats), 100 mg/kg PQ plus 66 µg/kg penehyclidine hydrochloride treatment group (30 rats). The two treatment groups were executed respectively at 36 h, 72 h and 7 d. Lung tissues were used to assess histopathological change by HE staining. The level of MMP-2, caveolin-1 and HYP were detected in the lung homogenate. The serum and BALF contents of ET were measured.

RESULTSPathology inspection confirmed that the model of acute rat pulmonary injury were duplicated successfully. The level of MMP-2, HYP in lung tissues and the serum and BALF ET contents in PQ group were (1.77 ± 0.40) µg/g, (2.91 ± 0.79) µg/g, (505.23 ± 124.69) µg/ml, (640.38 ± 136.60) µg/ml. The level of those was higher than that in control group [(0.95 ± 0.66) µg/g, (1.48 ± 0.69) µg/g, (95.48 ± 46.01) µg/ml, (200.40 ± 88.39) µg/ml, P < 0.05]; The above-mentioned index in two treatment groups was lower than that in PQ group (P < 0.05). The caveolin-1 content [(1.77 ± 0.82) µg/g] in PQ group was lower than that in control group [(5.39 ± 1.68) µg/g, P < 0.05]. The level of caveolin-1 in two treatment groups was higher than that in PQ group (P < 0.05).

CONCLUSIONPenehyclidine hydrochloride can decrease the level of MMP-2, HYP in lung tissues and the ET in serum and BALF, increase that of caveolin-1 and lessen the damage induced by paraquat.

Acute Lung Injury ; chemically induced ; drug therapy ; Animals ; Caveolin 1 ; metabolism ; Endothelins ; metabolism ; Hydroxyproline ; metabolism ; Male ; Matrix Metalloproteinase 2 ; metabolism ; Paraquat ; toxicity ; Quinuclidines ; therapeutic use ; Rats ; Rats, Wistar

BACKGROUNDThe mammalian target of rapamycin (mTOR) pathway, a key cellular signaling pathway associated with various cellular functions, has distinct roles in the inflammatory process. In this study, the mTOR inhibitor rapamycin (Rapa) was used to test whether inhibition of mTOR activation attenuates lipopolysaccharide (LPS)-induced acute lung injury (ALI) in a murine model.

METHODSMice pretreated with Rapa or vehicle were given LPS intratracheally. Local cell numbers and inflammatory cytokines present in the bronchoalveolar lavage fluid (BAL), wet-to-dry weight ratio, histopathology of the lungs, and survival were evaluated.

RESULTSThe phosphorylation of S6, a major downstream target of mTOR, had a 3-fold increase in lung tissue after LPS stimulation, but the increase was blocked by Rapa. Rapa reduced the levels of TNF-α (LPS vs. LPS + Rapa, (1672.74 ± 193.73) vs. (539.17 ± 140.48) pg/ml, respectively; P < 0.01) and IL-6 (LPS vs. LPS + Rapa: (7790.88 ± 1170.54) vs. (1968.57 ± 474.62) pg/ml, respectively; P < 0.01) in the BAL fluid. However, Rapa had limited effects on the overall severity of ALI, as determined by the wet-to-dry weight ratio of the lungs, number of neutrophils in the BAL fluid, and changes in histopathology. In addition, Rapa failed to reduce mortality in the LPS-induced ALI model.

CONCLUSIONSWe confirmed that mTOR was activated during LPS-induced ALI and strongly inhibited by Rapa. Although Rapa reduced the levels of the mediators of inflammation, the overall severity and survival of the ALI murine model were unchanged.

Acute Lung Injury ; chemically induced ; drug therapy ; Animals ; Lipopolysaccharides ; Mice ; Mice, Inbred C57BL ; Phosphorylation ; Sirolimus ; pharmacology ; therapeutic use ; TOR Serine-Threonine Kinases ; drug effects

OBJECTIVETo investigate the effect of bone marrow mesenchymal stem cell (BMSC) transplantation on acute lung injury induced by paraquat (PQ) poisoning in rats, and to identify the optimal transplantation conditions.

METHODSTwo hundred female rats were randomly divided into six groups, i.e., PQ group (n = 15), BMSC treatment group 1 (n = 15 for each subgroup), BMSC treatment group 2 (n = 15 for each subgroup), BMSC control group 1 (n = 15 for each subgroup), BMSC control group 2 (n = 15), and normal control group (n = 5). In the PQ group, each rat was intraperitoneally injected with 20% PQ solution (15 mg/kg). In BMSC treatment group 1, each rat was injected via the caudal vein with 1×10(5), 10(6), 10(7)or 10(8) BMSCs (1 ml) after 6 hours of PQ exposure. In BMSC treatment group 2, each rat was injected via the caudal vein with 1×10(7) BMSCs (1 ml) after 1, 6, 12, or 24 hours of PQ exposure. In BMSC control group 1, each rat was injected via the caudal vein with 1×10(5), 10(6), 10(7), or 10(8) BMSCs (1 ml). In BMSC control group 2, each rat was injected via the caudal vein with 1×10(7) BMSCs (1 ml). In the normal control group, each rat was intraperitoneally injected with an equal volume of 0.9% saline. The lung wet/dry weight ratio and plasma tumor necrosis factor-α (TNF-α) and malondialdehyde (MDA) levels were measured at 1, 3, and 7 days after various treatments.

RESULTSCompared with the normal control group, the PQ group showed significantly higher lung wet/dry weight ratios at 3 and 7 days after PQ exposure and significantly higher plasma TNF-α and MDA levels at 1, 3, and 7 days after PQ exposure (P < 0.01). Compared with the PQ group, BMSC treatment group 1 showed significantly lower lung wet/dry weight ratios at 7 days after injection of 1×10(6) and 10(7) BMSCs, significantly lower plasma TNF-α levels at 3 and 7 days after injection of 1×10(5), 10(6), and 10(7) BMSCs, and significantly lower plasma MDA levels at 3 days after injection of 1×10(6) and 10(7) BMSCs and at 7 days after injection of 1×10(5), 10(6), and 10(7) BMSCs (P < 0.05 or P < 0.01). Compared with the PQ group, BMSC treatment group 2 showed significantly lower lung wet/dry weight ratios at 7 days after injection of BMSCs following 1, 6, and 12 hours of PQ exposure, significantly lower plasma TNF-α levels at 3 and 7 days after injection of BMSCs following 1, 6, and 12 hours of PQ exposure, and significantly lower plasma MDA levels at 3 days after injection of BMSCs following 6 hours of PQ exposure and at 7 days after injection of BMSCs following 1, 6, and 12 hours of PQ exposure (P < 0.01).

CONCLUSIONBMSCs have a protective effect on the lung in rats with PQ poisoning, and the effect is closely related to the transplantation time and number of transplanted BMSCs. After 6 hours of PQ exposure, intravenous injection of 1×10(7) BMSCs can result in significant decreases in lung wet/dry weight ratio and plasma TNF-α and MDA levels.

Acute Lung Injury ; chemically induced ; therapy ; Animals ; Bone Marrow Cells ; Bone Marrow Transplantation ; Female ; Male ; Mesenchymal Stem Cell Transplantation ; Paraquat ; poisoning ; Rats ; Rats, Sprague-Dawley