Expression of matrix metalloproteinases in lung tissue in a rat model of ventilator-induced lung injury
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Objective To investigate the balance between matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in the lung tissue in a rat model of ventilator-induced lung injury. Methods Thirty healthy male SD rats weighing 200-250g were randomly divided into 3 groups( n = 10 each) : group A spontaneous breathing; group B small tidal volume (VT = 7 ml·kg-1, RR = 40 bpm, FiO2=0.21) and group C large tidal volume (VT = 40 ml·kg-1, RR = 20 bpm, FiO2=0.21). The animals were mechanically ventilated for 4 h in group B and C. The lung injury was assessed by measurement of PaO2 /FiO2 . At the end of the experiment the animals were killed and the lungs were removed. The right lung was used for determination of the expression of mRNAs of MMP-2, MMP-9, TIMP-1 and TTMP-2 using RT-PCR and histologic examination. The left lung was weighed and then lavaged. The broncho-alveolar lavage fluid (BALF) was collected for total WBC and neutrophil counts and determination of total protein content and gelatinase activity. After lavage the left lung was heated at 60℃. The W/D lung weight ratio was calculated. Results PaO2/FiO2 was significantly lower after 4h mechanical ventilation in group C than in group A and B. The total WBC count and total protein content in BALF were significantly higher in group C than in group A and B. The W/D ratio of the left lung was significantly higher in group C than in group A and B. Microscopic examination showed that there were marked WBC infiltration and destructive changes of alveolar walls in group C. The levels of gelatinase (MMP-2 and MMP-9) activities in BALF were significantly higher in group C than in group A and B. The expression of the mRNA of MMP-2 and MMP-9 was significantly higher in group C than in group A and B, but there was no significant difference in the expression of the mRNA of TIMP-1 and TIMP-2 between group C and group A and B. Conclusion Large tidal volume ventilation can induce acute lung injury. MMP-2 and MMP-9 play an important role in the development of ventilator induced lung injury and the imbalance between MMPs and TIMPs contributes to the mechanism of ventilator-induced lung injury.Cite
Objective To investigate the expression of aquaporin 5(AQP5)in lung tissue in a rat model of ventilator-induced lung injury(VILI).Methods Seventy pathogen free male SD rats were anesthetized with intraperitoneal 10% chloral hydrate 3.5 ml/kg,trachcostomized and mechanically ventilated.The animals were randomly assigned into 7 groups(n = 10 each)according to the tidal volume(V_T),respiratory rate(RR)and duration of mechanical ventilation: group A spontaneous breathing; group B_1,B_2(V_T 7 ml/kg,RR 50 bpm,I:E1 : 3,duration 2 h,4 h); group C_1,C_2(V_T 20 ml/kg,RR 50 bpm,I: E 1 : 3,duration 2 h,4 h)and group D_1,D_2(V_T 40 ml/kg,RR 50 bpm,I: E 1 : 3,duration 2 h,4 h).The animals were killed at the end of mechanical ventilation.The lungs were removed for microscopic examination,and determination of wet to dry lung weight ratio(W/D ratio),PMN counts in broncho-alveolar lung lavage fluid(BALF)and expression of AQP5 mRNA and protein in lung tissue.Results The expression of AQP5 mRNA and protein was significantly down-regulated while W/D ratio and PMN counts in BALF were significantly increased in group C and D than in group A and B.Conclusion The down-regulation of AQP5 expression in lung tissue may be involved in the development of lung edema during mechanical ventilation.
Key words:
Pneumonia,ventilator-associated; Aquaporin 5; Lung
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Objective To study the effects of hyperoxia on ventilator-induced lung injury(VILI) in rats.Methods 48 healthy male SD rats were randomly divided into four groups:group A received conventional mechanical ventilation(VT=8 mL/kg) with room air,group B received the same tidal volume as group A with 100% O2,group C received large tidal volume(VT=40 mL/kg) with room air,group D received the same tidal volume as group C with 100% O2.Arterial blood gases were measured every one hour and oxygenation index(PaO2/FiO2) was calculated.The changes of lung histopathology were assessed by HE staining and observed under light microscope.Wet-to-dry weight ratio(W/D) of left lung,neutrophils and white blood cell(WBC) counts in BALF were measured.Tumor necrosis factor-α(TNF-α),interleukin-1β(IL-1β),and macrophage inflammatory protein-2(MIP-2) levels in BALF,malondialdehyde(MDA),myeloperoxidase(MPO),and superoxide dismutase(SOD) levels in the lung were assayed,respectively.Results Compared with the group C,the group D demonstrated more infiltrating neutrophils in the lung and more destructive changes in the alveolar wall.Meanwhile,the oxygenation index decreased,the WBC and neutrophils counts in BALF increased,and the W/D of left lung was higher in the group D with significant differences compared with the group C.Moreover,the BALF levels of TNF-α,IL-1β and MIP-2,the lung levels of MDA increased,and the lung levels of SOD decreased significantly in the group D compared with those in the group C.There were no statistical significant differences between the group B and group A in all parameters except that MDA levels increased and SOD levels decreased significantly in the group B.Conclusion Hyperoxia can increase lung injury induced in large tidal volume ventilation in rats,but has mininmal effects in conventional mechanical ventilation.
Hyperoxia
Malondialdehyde
Oxygenation index
White blood cell
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Objective:To investigate the effects of hyperoxic liquid on the expression of aquaporin-1(AQP-1) in lung tissue of rabbits with acute lung injury(ALI).Methods: Forty-five rabbits were randomly divided into three groups: control group(group A),ALI group(group B) and hyperoxic liquid group(group C).ALI model was established by an special impactor in group B and group C.The animals in group C were given Shuayangkang by intravenous infusion.Blood samples were taken for blood gas analysis at 0,0.5,1,2,4,6 h.The animals were killed after 6 h,the ratio of wet to dry lung weight was measured,and the changes of lung tissue were pathologically observed.The expression of AQP-1 was examined by immunohistochemical method.Results:The value of PaO2 and SpO2,and the expression of AQP-1 in lung tissue in group B decreased significantly compared with group A(P0.05),while the ratio of wet to dry lung weight increased significantly(P0.05).In group C,the values of PaO2 and SpO2,and the expression of AQP-1 increased significantly compared to those of group B(P0.05),the ratio of wet to dry lung weight increased significantly(P0.05).Conclusion:The hyperoxic liquid exerts protective effect on acute lung injury by regulating the expression of AQP-1 in lung tissue.
Aquaporin 1
Group A
Group B
Aquaporin 4
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【Objective】To explore the effects of ulinastatin(Uti) for lung in healthy rat with ventilation induced lung injury.【Method】Forty healthy SD rats were randomly divided into five groups,with eight animals in each:sham group(C); large tidal volume ventilation group(M); pretreatment of Uti with doses of 10 ku/kg(U1),50 ku/kg(U5),100 ku/kg(U10). Except C group,others received ventilation for 4 h(parameter setting:Vt=30 ml/kg,RR= 40 breaths/min,I/E=1∶3,Fio2=21%). After ventilated for 4 h,the histological changes of the lungs were observed under light microscope. The concentrations of proteins,the counts of the total leukocyte and the differential counts in BALF were determined. 【Result】①With 4 h ventilated,PaO2 in the M group were significantly reduced compared with baseline values. Compared with C group,the lung W/D ratio; the level of proteins; the total numbers of leukocytes and leukocyte differential counts in BALF were great elevated. ②Prior treatment with Uti lessened all above index in different degrees. There were no statistical differences between the U1 group and the M group,but the differences between the U5 and U10 group with M group were distinct.【Conclusion】Uti could attenuate the lung injury from high tidal volume ventilation through suppressing the recruitment and activation of neutrophil and reducing the proteinum effusion for pneumoangiogram. The effects of lung in rat are dose dependent.
Ulinastatin
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Objective To investigate the expression and significance of Beclin-1 and nuclear factor-κB (NF-κB) in a rat model of ventilator-induced lung injury (VILI).Methods Thirty healthy SD rats were randomly divided into three groups (each 10 rats):control group (group A,no ventilation),conventional ventilation group (group B,VT=10 ml/kg),and lung injury group (group C,VT =40 ml/kg).After anesthesia and tracheotomy were installed,rats received ventilation with different volumes for 4 h.Thus rats were killed by exsanguinations.The lung wet/dry weight,myeloperoxidase (MPO) activity,and total protein level and counts of white blood cells (WBC) in broneho-alveolar lavage fluid (BALF) were tested.The expression of Beclin-1 and NF-κB was detected by Western blotting.Results After injurious ventilation for 4 h,the level of lung wet/dry weight,total protein level,MPO activity and counts of WBC were 6.13 ± 0.37,(4.12 ±0.29) g/ml,(5.89 ±0.75) × 106/L,and (6.75 ± 1.18) U/g respectively.The average values of Beclin-1 and NF-κB proteins were 1.21 ±0.14 and 0.47 ±0.11 respectively,and there was a negative correlation between the two proteins.Conclusion Tidal volume mechanical ventilation can induce lung tissue damage and autophagy can inhibit the activity of NF-κB to protect lung tissue to avoid VILI in rats.
Key words:
Ventilator-induced lung injury; Autophagy; Nuclear factor-κB
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Objective:To investigate the role of gelatinases in the pathogenesis of acute lung injury (ALI) induced by lipopolysaccaride (LPS). Methods:Thirty-two rats were randomly divided into saline control group and different LPS groups (2 h, 4 h and 6 h after LPS challenge). Lung injury was quantified by measurements of PaO 2/FiO 2, lung permeability index (LPI) and histopathologic scoring. Samples obtained from bronchoalveolar lavage (BAL) fluid were compared for the presence of gelatinases by gelatin zymography. Immunohistochemical staining of the type-Ⅳ collagen was performed on sections of lung specimens. Results: The animals treated with LPS for 4 h and 6 h had developed ALI with respiratory failure as evidenced by a decrease of PaO 2/FIO 2 and an increase of LPI and histopathologic total lung injury score (all P0.01 versus the control group). MMP-2 (gelatinase A) activity was significantly increased at 2nd h after LPS (P 0.01 versus the control group), and not further changed at 4th h or 6th h after LPS (P0.05 versus 2 h group). MMP-9 (gelatinase B) was not essentially detectable in rats treated with saline, but great in rats treated with LPS for 2 h, and further enhanced at 4th h and 6th h after LPS (P0.01 versus 2 h group). MMP-9 activity was significantly correlated with PaO 2/FiO 2, LPI and the histopathologic total lung injury score (r=-0.69, r=0.80, r=0.71, respectively, all P0.05). MMP-2 activity had a correlation with the histopathologic total lung injury score (r=0.50, P0.05 ). Staining for type Ⅳ collagen showed the basement membrane (BM) in lung tissue was disrupted by LPS whereas no disruption was detected in the control group. Conclusion:Gelatinases (MMP-2 and MMP-9) play a role in the pathogenesis of LPS-induced acute lung injury, at least in part, through the degradation of the basement membrane in lung tissue.
Gelatinases
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OBJECTIVE To evaluate the effect of lung protective ventilation strategy on pulmonary inflammatory response in acute respiratory distress syndrome (ARDS). METHODS The ARDS rabbit model was duplicated by saline alveolar-lavage. The rabbits were divided into six groups: (1) normal control group (N group); (2) ARDS group (M group); (3) low-volume with best end-expiratory pressure (PEEP, A group) group: tidal volume (V(T)) 6 ml/kg, PEEP 2 cm H(2)O greater than the pressure of lower inflection point in pressure-volume curve (P(LIP)); (4) normal-volume with best PEEP group (B group): V(T) 6 ml/kg, and PEEP P(LIP) + 2 cm H(2)O; (5) low-volume with high PEEP group (C group): V(T) 6 ml/kg, and PEEP 15 cm H(2)O; and (6) high-volume with zero PEEP group (D group): V(T) 20 ml/kg. Lung wet/dry weight ratios (W/D) were recorded to evaluate lung injury. After 4 h of ventilation, lung homogenates were prepared to detect nuclear factor-kappaB (NF-kappaB) activity by electrophoretic mobility gel shift assay (EMSA), tumor necrosis factor-alpha (TNF-alpha) and interleukin-10 (IL-10) levels by enzyme-linked immunosorbent assay (ELISA) and their mRNA expression by reverse transcriptase-polymerase chain reaction (RT-PCR). Myeloperoxidase (MPO) and malondialdehyde (MDA) in lung homogenates were also assessed. RESULTS After 4 h ventilation, W/D in A group (5.6 +/- 1.1) were significantly lower than those in B group, C group and D group (6.6 +/- 0.8, 6.6 +/- 1.0, 6.9 +/- 1.0, all P < 0.05). But there was no difference between A group and M group (5.8 +/- 0.5). NF-kappaB activity was the highest in D group, and that in A group was 331 +/- 113, which was decreased significantly as compared with B, C and D groups (455 +/- 63, 478 +/- 74, 645 +/- 162, all P < 0.05). The mRNA expression of TNF-alpha and IL-10 and their concentrations in lung homogenates in A group were lower than those in B, C and D groups. In A group, the concentrations of MPO and MDA in lung homogenates were significantly lower than those in B, C and D groups. CONCLUSION Lung protective ventilation strategy can inhibit lung inflammation and may improve lung injury in ARDS, but low tidal volume with high PEEP may increase lung inflammation.
Positive End-Expiratory Pressure
Diffuse alveolar damage
Malondialdehyde
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Objective To investigate the changes in the expression of macrophage migration inhibitory factor （MIF） mRNA in a rat model of ventilator-induced lung injury. Methods Thirty adult male Sprague-Dawley rats, weighing 235-260 g, were randomly divided into 3 groups （ n = 10 each） using a random number table： con- trol group （group C）, small tidal volume （VT ） mechanical ventilation group （group S） and large tidal volume me- chanical ventilation group （group L） . The animals were anesthetized with intraperitoneal ketamine 100 mg/kg, mi- dazolam 0.2 mg/kg and atropine 1.0 mg/kg. The rats were tracheostomized and spontaneous breathing was main- tained in group C, while the rats were tracheostomized and mechanically ventilated for 4 h in groups S and L. The tidal volume was 7 ml/kg （group S） or 40 ml/kg （group L）,I： E was 1 ： 1, RR was 80 bpm and FiO2 was 100% . At 4 h of spontaneous breathing or mechanical ventilation, broncho-alveolar lung lavage fluid （BALF） was collect- ed for determination of the total protein concentration; white blood cell （WBC） counts and concentrations of MIF, IL-6 and IL-1β （by ELISA）. Then the rats were sacrificed and the lungs removed for microscopic examination and for determination of wet to dry lung weight ratio （W/D ratio） and expression of MIF mRNA （by RT-PCR）. Results Compared with C and S groups, WBC counts, concentrations of total protein, MIF, IL-6 and IL-1β in BALF, and W/D ratio and expression of MIF mRNA in lung tissues were significantly increased in group L （P 〈 0.05）. There was no significant difference in the indexes mentioned above between group C and group S （ P 〉 0.05 ）. The pathological changes occurred in group L. Conclusion The up-regulation of MIF mRNA expression in lung tissues may be involved in the development of ventilator-induced lung injury in rats.
Key words:
Respiration, artificial; Respiratory distress syndrome, adult; Macrophage migration-in-
Intraperitoneal injection
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：Objective To investigatethe role of p38 MAPK pathway in the expression of high mobility group box 1 (HMGB1) inlung tissue in a rat model of ventilator-induced lung injury. Method Twenty-fonr healthySprague Dawley (SD) rats were randomly divided into 3 groups (n = 8 each) : group A,spontaneous breathing; group B, small tidal volume ventilation (Vt = 8 mL/kg) and group C,high tidal volume ventilation (Vt = 40 mL/kg). 1he animals in group B and C weremechanically ventilated for 4 hours and all animals were sacri-riced. The lungs wereremoved for: (1) lung lavage and determination of total protein contnt and WBC andneu-trophil counts in broncho-alveolar lavage fluid (BALF) ; (2) determination of W/D lungweight ratio and myelop-erexidnse (MPO) activity; (3) detennination of HMGB1 protein andmRNA expression and p38 MAPK activity in lung tissue. Differences within the groups wereanalyzed using One way ANOVA. Results The inflammatory re-sponse as evidenced by totalprotein (1.77 ± 0.68) g/L and WBC (106.55 ± 28.17) × 10~7/L in BALF, W/D lung weightratio (7.16±1.02) and MPO activity (3.94±1.21) U/g were significantly higher in group Ccom-pared with group A (P 0.05). Conclusions High tidal volume ventilation in-daces acute lunginjury, which may be related with upregulation of HMGB1 expression through p38 MAPK signalpathway.
HMGB1
High-mobility group
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