Neutrophil Proteinases in Hydrochloric Acid- and Endotoxin-Induced Acute Lung Injury: Evaluation of Interstitial Protease Activity by in situ Zymography

Louw, Andry Van de; Jean, Daniel; Frisdal, Éric; Cerf, Charles; d’Ortho, Marie Pia; Baker, Andrew H.; Lafuma, C.; Duvaldestin, P.; Harf, Alain; Delclaux, Christophe

doi:10.1038/labinvest.3780406

Cited by 25 publications

(16 citation statements)

References 41 publications

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“…To determine the extent of lung leukocyte recruitment and protein permeability, we quantified total cell count, neutrophil count, and protein concentrations in BAL. At baseline, these variables were consistent with previously reported data ( Figure 5) (7,25,26). We gave a 15-min infusion of isosmolar buffer, then we followed 0.5 h later with intratracheal acid instillation.…”

Section: Anesthetized Ratsupporting

confidence: 79%

Inhibition of Acid-induced Lung Injury by Hyperosmolar Sucrose in Rats

Safdar

Yiming

Grünig

et al. 2005

Am J Respir Crit Care Med

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Rationale: Acid aspiration causes acute lung injury (ALI). Recently, we showed that a brief intravascular infusion of hyperosmolar sucrose, given concurrently with airway acid instillation, effectively blocks the ensuing ALI. Objectives: The objective of the present study was to determine the extent to which intravascular infusion of hyperosmolar sucrose might protect against acid-induced ALI when given either before or after acid instillation. Methods: Our studies were conducted in anesthetized rats and in isolated, blood-perfused rat lungs. We instilled HCl through the airway, and we quantified lung injury in terms of the extravascular lung water (EVLW) content, filtration coefficient (K fc ), and cell counts and protein concentration in the bronchoalveolar lavage. We infused hyperosmolar sucrose via the femoral vein. Results: In anesthetized rats, airway HCl instillation induced ALI as indicated by a 52% increase of EVLW and a threefold increase in K fc . However, a 15-min intravenous infusion of hyperosmolar sucrose given up to 1 h before or 30 min after acid instillation markedly blunted the increases in EVLW, as well as the increases in cell count, and in protein concentration in the bronchoalveolar lavage. Hyperosmolar pretreatment also blocked the acid-induced increase of K fc . Studies in isolated perfused lungs indicated that the protective effect of hyperosmolar sucrose was leukocyte independent. Conclusions: We conclude that a brief period of vascular hyperosmolarity protects against acid-induced ALI when the infusion is administered shortly before, or shortly after, acid instillation in the airway. The potential applicability of hyperosmolar sucrose in therapy for ALI requires consideration.Keywords: acid aspiration syndrome; extravascular lung water; filtration coefficient; leukocyte count; lung blood contentThe aspiration of gastric acid, which is prone to occur in conditions such as drug overdose, stroke, and general anesthesia, is an increasingly important cause of acute lung injury (ALI), which is associated with high rates of morbidity and mortality (1). In animal models of acid-induced ALI, intratracheal acid instillation induces lung leukocyte sequestration that characteristically precedes pulmonary edema (2, 3). Accordingly, proposed therapeutic strategies include protocols that either inhibit lung leukocyte accumulation (4-8) or reduce alveolar liquid accumulation (9-11). However, strategies for lung endothelial barrier strengthening remain inadequately considered. The lung endothelial barrier, which is established by intercellular junctional proteins of endothelial cells lining lung microvessels, protects against excessive lung liquid accumulation. Decreased lung endothelial barrier function increases transmicrovascular liquid flux, thereby promoting pulmonary edema, which is a hallmark of ALI. Although it has long been known that airway acid instillation injures the lung microvascular barrier (12), relevant therapeutic strategies are not known. This article considers the possibility that...

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Section: Anesthetized Ratsupporting

confidence: 79%

Inhibition of Acid-induced Lung Injury by Hyperosmolar Sucrose in Rats

Safdar

Yiming

Grünig

et al. 2005

Am J Respir Crit Care Med

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“…The authors have previously shown that an inflammatory response occurs in both LPS-and bacteria-instilled lungs, at least in term of TNF-a secretion [7,17], and that its local secretion participates to alveolar liquid clearance [7,18]. Therefore, it could explain the absence of significant persistent oedema in these models at the 24th hour.…”

Section: Discussionmentioning

confidence: 97%

Induction of type-IIA secretory phospholipase A2 in animal models of acute lung injury

Attalah

Wu²,

Alaoui-El-Azher³

et al. 2003

Eur Respir J

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The aim of this study was to evaluate the presence of type-II secretory phospholipase A2 (sPLA2-IIA) in alveolar space and its possible role in the destruction of surfactant in three rat models of acute lung injury.Alveolar instillation of either lipopolysaccaride or live Pseudomonas aeruginosa resulted in a significant increase in lung oedema and in a decrease in static compliance of the respiratory system together with alveolar-neutrophil influx as compared with healthy control rats.The upregulation of messenger ribonucleic acid and sPLA2-IIA by the lung was evident. This was associated with surfactant degradation and a decrease in large:small ratio of surfactant aggregates in bacteria-instilled rats. A negative correlation between compliance and sPLA2-IIA activity in bronchoalveolar lavage fluid was shown. By contrast, during alpha naphthylthiourea-induced injury, neither alveolar-neutrophil influx nor increase in sPLA2-IIA activity was observed.Additional experiments in rats treated with a specific inhibitor of type-II secretory phospholipase A2 activity (3 acetamine-1-benzyl-2 ethylindolyl-5 oxy; propane phosphonic acid (LY311727)) demonstrated no improvement in physiological parameters despite a biochemical effect, suggesting that its activity is only one of the multiple factors involved in the pathophysiology of lung injury. Surfactant degradation has been shown to be one of the key features of acute respiratory distress syndrome (ARDS) leading to a decrease in both lung compliance and oxygenation [1,2]. Consequently, several clinical trials have evaluated the effect of exogenous surfactant administration. However, the relative inefficacy of this approach has been attributed to insufficient alveolar delivery of exogenous surfactant and/or to its inhibition/degradation by alveolar enzymatic activities [2]. Along this line, type-IIA secretory phospholipase A2 (sPLA2-IIA), an enzyme produced by alveolar inflammatory cells during acute lung injury (ALI), has previously been shown to participate in surfactant degradation [3][4][5]. sPLA2-IIA belongs to a superfamily of enzymes that hydrolyses the sn-2 fatty acyl ester bond of phosphoglycerides, generating lysophospholipids and free fatty acids [6]. These enzymes play a major role in the induction of inflammatory reactions via the synthesis of lipid mediators, such as platelet activating factor, leukotrienes and prostaglandins [5,6]. A number of studies suggest that sPLA2-IIA is involved in the pathogenesis of inflammatory diseases including ARDS. Indeed, a clinical trial demonstrated an increased sPLA2-IIA activity in bronchoalveolar lavage (BAL) fluid of patients with ARDS whose levels were positively correlated with disease severity [5].The assessment of the role of sPLA2-IIA activity in terms of both surfactant and compliance impairment is of major value, since its inhibition could constitute a therapeutic approach. Therefore, the aims of this study were to assess whether correlation could be established between indexes of injury (lung oedema, art...

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“…The BAL fluid (198)(199)(200) and plasma (201,202) of patients with ALI/ ARDS have elevated concentrations of MMPs, which correlate with clinical severity (203), and MMP inhibition is protective in experimental models of lung injury (191,196,204,205), although there is some conflicting data in the literature (206,207). Importantly, the implicated MMPs are derived from neutrophils (197) as well as alveolar macrophages (208).…”

Section: Matrix Metalloproteinasesmentioning

confidence: 91%