Dexamethasone treatment attenuates early seawater instillation-induced acute lung injury in rabbits

doi:10.1016/j.phrs.2006.01.006

Pharmacological Research

Volume 53, Issue 4, April 2006, Pages 372-379

https://doi.org/10.1016/j.phrs.2006.01.006 Get rights and content

Abstract

There is very little evidence on the value of giving corticoids in cases of seawater drowning induced acute lung injury/acute respiratory distress syndrome (ALI/ARDS). Therefore, this study aimed to investigate whether dexamethasone treatment can attenuate seawater instillation-induced acute lung injury in rabbits. Seawater (4 ml/kg body weight) was instilled into the lower trachea of ventilated, anesthetized rabbits. Then these rabbits were assigned randomly 20 min later to receive intravenous injection of 1 mg/kg body weight of dexamethasone (dissolving in 2 ml of normal saline) or 2 ml of normal saline. All animals demonstrated immediate drops in arterial oxygen tension (PaO₂) and the total thoracic compliance, which were significantly improved after 2 h of dexamethasone treatment. Histopathological study also indicated that dexamethasone treatment markedly attenuated lung histopathological changes, alveolar hemorrhage and inflammatory cells infiltration with evidence of decreasing of myeloperoxidase (MPO) activity and tumor necrosis factor-α (TNF-α) concentration in lung tissue. In addition, dexamethasone treatment reduced extravascular lung water and lung epithelial–endothelial barrier permeability, up-regulated the expression of surfactant protein-A (SP-A) and α-epithelial Na⁺ channel, and increased Na⁺/K⁺-adenosine triphosphatase (Na⁺/K⁺-ATPase) activity and Na⁺/K⁺-ATPase-α1 protein abundance. Thus, these data indicate that dexamethasone treatment might be of benefit in patients with seawater aspiration-induced ALI.

Introduction

The World Health Organization (WHO) estimates the annual worldwide incidence of death by drowning to be about 400,000. Furthermore, drowning is a leading cause of accidental death in children [1]. Current data suggest that hypoxemia is the major pathophysiologic abnormality after drowning. In 85–90% cases, the hypoxemia is related to aspiration. Water aspiration can induce acute lung injury (ALI) and its more severe form, the acute respiratory distress syndrome (ARDS), which are characterized by an acute inflammatory process in airspaces and lung parenchyma. These syndromes are manifestations of the loss of barrier function of the alveolar epithelial and pulmonary capillary endothelial cells [2]. Administration of corticoids is a drug option in the therapy of ALI/ARDS, according to present pathophysiological concepts. However, definitive evidence to support their use is lacking [3]. There is also very little evidence on the value of giving corticoids in cases of seawater drowning induced ALI/ARDS [4].

Therefore, there were three objectives to investigate in this study using a rabbit model of intratracheal instillation of seawater-induced ALI. The first objective was to determine whether dexamethasone would improve gas exchange and the total thoracic compliance. The second objective was to study whether dexamethasone would relieve the injury of lung endothelial cell and alveolar epithelial cell and the airspace inflammation. In addition, clinical data have demonstrated that the presence of maximal alveolar fluid clearance (AFC) is associated with improved mortality in patients with ALI and ARDS [5], [6]. The current working model of the lung fluid balance indicates that Na⁺ enters alveolar epithelial cells at apical surface via predominantly epithelial Na⁺ channels (ENaC) and is pumped out by basolateral Na⁺/K⁺-adenosine triphosphatase (Na⁺/K⁺-ATPase), which produces a unidirectional Na⁺ transport and resulting fluid absorption from the alveolar space [7]. Thus, the final objective was to examine whether dexamethasone would decrease extravascular lung water (ELW) and up-regulate the expression of ENaC and Na⁺/K⁺-ATPase in lung tissue.

Section snippets

Animal preparation

All animal experiments were undertaken with protocols approved by the Naval General Hospital of PLA, Committee on Animal Research. Thirty healthy male New Zealand white rabbits weighing 2.35 ± 0.36 kg, range 2.1–2.6 kg (Keyu animal feeding center, Beijing, China, Certificate Number: SCXK-jing-2002-0005) were randomly allocated to three groups: control group (CG), dexamethasone treatment group (DG) and normal group (NG).

Experimental protocols

CG (n = 12): The rabbits were anesthetized with 20% urethane (1.0 g/kg) injected

Effect of dexamethasone treatment on PaO₂, Cst and Cdyn

As shown in Fig. 1, seawater instillation caused a marked decrease in the PaO₂ (Fig. 1A), Cst (Fig. 1B) and Cdyn (Fig. 1C), which could be partly improved by dexamethasone treatment. At 180 min post seawater instillation, the DG's PaO₂ was 253 ± 77 mmHg, which was significantly higher than the CG's (149 ± 68 mmHg) (p < 0.01, Fig. 1A). At the same point, the DG's Cst (1.52 ± 0.16 ml/cmH₂O) or Cdyn (1.13 ± 0.15 ml/cmH₂O) was also significantly higher than the CG's Cst (0.97 ± 0.11 ml/cmH₂O) or Cdyn (0.85 ± 0.13 ml/cmH

Discussion

Current evidence indicates that short-duration, high-dose corticosteroids therapy is not effective for early ARDS or severe sepsis. But the cause of ARDS is complex, this result is not suitable for all subgroups with ARDS. An evidence review of corticosteroids for ARDS found that certain subgroups with early ALI/ARDS do benefit from corticosteroids. There are (1) Level I evidence that high-dose corticosteroids benefit patients suffering P. carinii pneumonia and (2) Level II evidence that

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¹: Both these authors contributed equally to this work.

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Dexamethasone treatment attenuates early seawater instillation-induced acute lung injury in rabbits

Abstract

Introduction

Section snippets

Animal preparation

Experimental protocols

Effect of dexamethasone treatment on PaO2, Cst and Cdyn

Discussion

Resuscitation

Crit Care Clin

Clin Chest Med

Cytokine Growth Factor Rev

Crit Care Clin

The acute respiratory distress syndrome

N Engl J Med

Glucocorticoids and acute lung injury

Crit Care Med

Towards evidence based emergency medicine: best BETs from the Manchester Royal Infirmary. Corticosteroids in the management of near-drowning

Emerg Med J

Intact epithelial barrier function is critical for the resolution of alveolar edema in humans

Am Rev Respir Dis

Alveolar fluid clearance is impaired in the majority of patients with acute lung injury and the acute respiratory distress syndrome

Am J Respir Crit Care Med

Lung epithelial fluid transport and the resolution of pulmonary edema

Physiol Rev

Respiratory monitoring

JAMA

Measurement of pulmonary edema

Circ Res

Transvascular flux and tissue accrual of Evans blue: effects of endotoxin and histamine

J Lab Clin Med

Inhaled and intravenous corticosteroids both attenuate chlorine gas-induced lung injury in pigs

Acta Anaesthesiol Scand

Polymorphonuclear leukocytes: their role as central cellular elements in shock pathogenesis

Shock

Neutrophils and acute lung injury

Crit Care Med

Absence of inflammatory lung injury in rabbits challenged intravascularly with complement- derived chemotactic factors

Am Rev Respir Dis

Effects of leukotriene B4 in the human lung. Recruitment of neutrophils into the alveolar spaces without a change in protein permeability

J Clin Invest

Effect of dexamethasone treatment on PaO₂, Cst and Cdyn