DDAH1 Promotes Lung Endothelial Barrier Repair by Decreasing Leukocyte Transendothelial Migration and Oxidative Stress in Explosion-Induced Lung Injury

Abstract

Explosion-induced injury is the most commonly encountered wound in modern warfare and incidents. The vascular inflammatory response and subsequent oxidative stress are considered the key causes of morbidity and mortality among those in blast lung injury. It has been reported dimethylarginine dimethylaminohydrolase 1 (DDAH1) plays important roles in regulating vascular endothelial injury repair and angiogenesis, but its role in explosion-induced injury remains to be explained. To explore the mechanism of vascular injury in blast lung, 40 C57BL/6 wild type mice and 40 DDAH1 knockout mice were randomly equally divided into control group and blast group, respectively. Body weight, lung weight, and dry weight of the lungs were recorded. Diffuse vascular leakage was detected by Evans blue test. The serum inflammatory factors, nitric oxide (NO) contents, and ADMA level were determined through ELISA. Hematoxylin-eosin staining and ROS detection were performed for histopathological changes. Western blot was used to detect the proteins related to oxidative stress, cell adhesion molecules and leukocyte transendothelial migration, vascular injury, endothelial barrier dysfunction, and the DDAH1/ADMA/eNOS signaling pathway. We found that DDAH1 deficiency aggravated explosion-induced body weight reduction, lung weight promotion, diffuse vascular leakage histopathological changes, and the increased levels of inflammatory-related factors. Additionally, DDAH1 deficiency also increased ROS generation, MDA, and IRE-1α expression. Regarding vascular endothelial barrier dysfunction, DDAH1 deficiency increased the expression of ICAM-1, Itgal, Rac2, VEGF, MMP9, vimentin, and N-cadherin, while lowering the expression of occludin, CD31, and dystrophin. DDAH1 deficiency also exacerbated explosion-induced increase of ADMA and decrease of eNOS activity and NO contents. Our results indicated that explosion could induce severe lung injury and pulmonary vascular insufficiency, whereas DDAH1 could promote lung endothelial barrier repair and reduce inflammation and oxidative stress by inhibiting ADMA signaling which in turn increased eNOS activity.

Association between serum uric acid levels and lung function in the NHANES cohort (2007–2012): A cross‐sectional analysis of a diverse American population

“…Another study conducted in Japan, 13 sue detriment and the impairment of alveoli and airways. [25][26][27][28][29] UA positively correlated with inflammatory markers, including TNFα, C-reactive protein, and IL-6. These markers of inflammation have the potential to cause damage to vascular endothelial cells.…”

“…An elevation in UA has been demonstrated to correlate with oxidative stress due to heightened xanthine oxidase activity and diminished nitric oxide levels, increasing both superoxide and reactive ROS production. Reactive oxygen species can induce oxidative stress, resulting in lung tissue detriment and the impairment of alveoli and airways 25–29 . UA positively correlated with inflammatory markers, including TNF‐α, C‐reactive protein, and IL‐6.…”

Tanshinone IIA inhibits ischemia-reperfusion-induced inflammation, ferroptosis and apoptosis through activation of the PI3K/Akt/mTOR pathway

“…Lung water content 23 48 h after I/R, the mice were anesthetized with 2% pentobarbital sodium (1.5 mL/kg, Sinopharm Group Co., Ltd, China). After the mice were killed, blood and lung samples were collected.…”

Anthrahydroquinone‑2,6‑disulfonate attenuates PQ‑induced acute lung injury through decreasing pulmonary microvascular permeability via inhibition of the PI3K/AKT/eNOS pathway

“…In ARDS, there is increased permeability of the pulmonary vasculature to circulating fluids, macromolecules and leukocytes due to a severe inflammatory response that disrupts the endothelial barrier, leading to alveolar filling and neutrophilic in-flow. This leads to the high mortality rate of ARDS ( 13 - 15 ).…”

“…In ARdS, there is increased permeability of the pulmonary vasculature to circulating fluids, macromolecules and leukocytes due to a severe inflammatory response that disrupts the endothelial barrier, leading to alveolar filling and neutrophilic in-flow. This leads to the high mortality rate of ARdS (13)(14)(15). Anthrahydroquinone-2,6-disulfonate (AH 2 QdS) is a reducing agent that has previously been demonstrated to bind specifically to PQ to reduce its levels in the body and thereby improve its survival (16)(17)(18)(19).…”