BACKGROUND: Accumulating evidence shows that angiotensin II (ANG II) can be generated locally in the lung tissue and may have autocrine and/or paracrine actions on the cellular level. In addition, ANG II precursor, angiotensinogen, as well as ANG II type 1 receptor (AT(1)), are also expressed in the lung tissue. Recent studies revealed that ANG II promoted acute lung injury induced by acid aspiration or sepsis, and that ANG II receptor blockade had a protective effect against acute lung injury. Therefore, the authors hypothesized that ventilator-induced lung injury might also be exacerbated by local ANG II action, and that ANG II receptor blockade would protect the lung from ventilator-induced lung injury. MATERIALS AND METHODS: Forty Sprague Dawley rats weighing 300-350 g were randomly divided into the following experimental groups (10 rats in each group): (1) control group: rats were unventilated; (2) LVT (low volume ventilation) group: rats were ventilated with 8 mL/kg tidal volume room air for 2 h; (3) HVT (high volume ventilation) group: rats were ventilated with 40 mL/kg tidal volume room air for 2 h; (4) HVT + Losartan group: rats were pretreated with Losartan (30 mg/kg, i.p.) prior to high volume ventilation. The samples of pulmonary tissue and lung lavage fluid were collected after experiments. The expression of angiotensinogen and AT(1) receptor mRNA in lung tissue was measured by reverse transcriptase-polymerase chain reaction. Apoptosis of the lung cells was assayed with terminal deoxynucleodityl transferase-mediated nick-end labeling method. Lung pathological changes were examined with optical microscopy. Total protein, wet/dry ratios (W/D), myeloperoxidase (MPO) activity, and neutrophil counts of the lung tissue or lavage fluid were measured with corresponding methods. RESULTS: Compared with control or LVT, HVT caused significant ventilator-induced lung injury and increased the expression of angiotensinogen and AT(1) receptor mRNA in the lung. Total protein, the number of apoptotic cells, W/D ratio, MPO activity, and neutrophil counts were significantly higher in the HVT group than in the LVT or control group. Pretreatment with Losartan attenuated ventilator-induced lung injury and prevented the increase in total protein, the number of apoptotic cells, W/D ratio, MPO, and neutrophil counts caused by high volume ventilation. CONCLUSION: Our study indicates that HVT causes remarkable lung injury and up-regulates angiotensinogen and AT(1) receptor expression of in the lung, and that Losartan, a selective inhibitor of subtype AT(1) receptors for angiotensin II, can relieve acute lung injury caused by high volume ventilation.
BACKGROUND: Accumulating evidence shows that angiotensin II (ANG II) can be generated locally in the lung tissue and may have autocrine and/or paracrine actions on the cellular level. In addition, ANG II precursor, angiotensinogen, as well as ANG II type 1 receptor (AT(1)), are also expressed in the lung tissue. Recent studies revealed that ANG II promoted acute lung injury induced by acid aspiration or sepsis, and that ANG II receptor blockade had a protective effect against acute lung injury. Therefore, the authors hypothesized that ventilator-induced lung injury might also be exacerbated by local ANG II action, and that ANG II receptor blockade would protect the lung from ventilator-induced lung injury. MATERIALS AND METHODS: Forty Sprague Dawley rats weighing 300-350 g were randomly divided into the following experimental groups (10 rats in each group): (1) control group: rats were unventilated; (2) LVT (low volume ventilation) group: rats were ventilated with 8 mL/kg tidal volume room air for 2 h; (3) HVT (high volume ventilation) group: rats were ventilated with 40 mL/kg tidal volume room air for 2 h; (4) HVT + Losartan group: rats were pretreated with Losartan (30 mg/kg, i.p.) prior to high volume ventilation. The samples of pulmonary tissue and lung lavage fluid were collected after experiments. The expression of angiotensinogen and AT(1) receptor mRNA in lung tissue was measured by reverse transcriptase-polymerase chain reaction. Apoptosis of the lung cells was assayed with terminal deoxynucleodityl transferase-mediated nick-end labeling method. Lung pathological changes were examined with optical microscopy. Total protein, wet/dry ratios (W/D), myeloperoxidase (MPO) activity, and neutrophil counts of the lung tissue or lavage fluid were measured with corresponding methods. RESULTS: Compared with control or LVT, HVT caused significant ventilator-induced lung injury and increased the expression of angiotensinogen and AT(1) receptor mRNA in the lung. Total protein, the number of apoptotic cells, W/D ratio, MPO activity, and neutrophil counts were significantly higher in the HVT group than in the LVT or control group. Pretreatment with Losartan attenuated ventilator-induced lung injury and prevented the increase in total protein, the number of apoptotic cells, W/D ratio, MPO, and neutrophil counts caused by high volume ventilation. CONCLUSION: Our study indicates that HVT causes remarkable lung injury and up-regulates angiotensinogen and AT(1) receptor expression of in the lung, and that Losartan, a selective inhibitor of subtype AT(1) receptors for angiotensin II, can relieve acute lung injury caused by high volume ventilation.
Authors: Harmony R Reynolds; Samrachana Adhikari; Claudia Pulgarin; Andrea B Troxel; Eduardo Iturrate; Stephen B Johnson; Anaïs Hausvater; Jonathan D Newman; Jeffrey S Berger; Sripal Bangalore; Stuart D Katz; Glenn I Fishman; Dennis Kunichoff; Yu Chen; Gbenga Ogedegbe; Judith S Hochman Journal: N Engl J Med Date: 2020-05-01 Impact factor: 91.245