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Updated: Sep 4, 2025
Fixed Volume or Fixed Pressure: A Murine Model of Hemorrhagic Shock
Published on: June 6, 2011
Shock lung is not "wet" but characterized as necroptotic inflammation in a mouse model of hypotension
Junyi Yu1, Che Xu2, Zongmei Wen3
1Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pa; Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, Pa; Department of Breast Neoplastic Surgery (25th Ward), Hunan Tumor Hospital, The Affiliated Tumor Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China.
Objectives:
Hypotension episodes before or after donor brain death are assumed to trigger hypoxia-reoxygenation, causing diffuse alveolar-capillary damage via necrosis. However, alveolar-capillary membranes have direct access to oxygen in alveoli. We hypothesized hypotension-induced lung injury is not diffuse alveolar-capillary damage but interstitial inflammation resulting from nonhypoxic lung ischemia and systemic responses to hypoxic extrapulmonary ischemia.
Methods:
The 4-hour hypotension model was established by subjecting C57BL/6J mice to 4-hour hypotension at 15 ± 5 mm Hg of mean artery pressure and resuscitated with whole shed blood and norepinephrine. Nonhypoxic lung ischemia model was established by 4-hour left pulmonary artery ligation. At 24 hours postprocedure, an arterial blood gas analysis and a gastroduodenal occult blood test were conducted. Lung samples were assessed for histology, cytokine transcripts, regulated cell death, and alveolar-capillary permeability.
Results:
The 4-hour hypotension model had an intraoperative mortality rate of 17.7% (41/231) and a stress-ulcer bleeding rate of 15.3% (29/190). No signs of alveolar flooding were observed in both models. Four-hour hypotension without stress ulcer showed normal oxygenation and permeability but increased interstitial infiltration, transcription of Tnf and Il1b, phosphorylation of MLKL and RIPK3, and cleaved caspase 3 compared with 4-hour pulmonary artery ligation and naïve control. Animals that developed stress ulcer presented with worse pulmonary infiltration, intracellular edema, and oxygenation but just slightly increased permeability. Immunoblotting showed significant upregulations of protein expression and phosphorylation of MLKL and RIPK3, cleaved Caspase-3, but not its prototype in 4-hour hypotension with stress ulcer.
Conclusions:
Hypotensive lung injury is essentially a nonhypoxic ischemia-reperfusion injury enhanced by systemic responses. It is predominated by necroptosis-induced inflammation rather than necrosis-induced diffuse alveolar-capillary damage.
