TORONTO—Although the acute respiratory distress syndrome (ARDS) primarily affects the lungs, multiple organ dysfunction syndrome (MODS) is the most common immediate cause of ARDS-related mortality. Some mechanical ventilatory strategies have been shown to lower the risk of MODS and death in ARDS patients, but how they achieve this effect has been unclear. However, recent work in a rabbit model of ARDS has identified one pathway that could mediate renal and small intestine damage following mechanical ventilation.[1] The research may partially explain why protective ventilatory strategies reduce mortality in ARDS patients; it also suggests new therapeutic targets for reducing ventilator-associated organ damage.

“Patients with ARDS … have a really high mortality rate—on the order of 40%, 50%,” noted principal author Arthur S. Slutsky, MD. “But, despite severe injury to the lungs, most patients who die don’t die from hypoxemia. They die because other organs start to fail: the kidney, the liver, the heart. And that’s been a bit of a conundrum.”

During the past decade, awareness has emerged that employing the wrong mechanical ventilation strategy might account for many of these deaths. “Mortality in ARDS can be reduced 22% by using a ventilatory strategy with smaller tidal volumes,” observed Dr. Slutsky, Professor of Medicine and Director of the Interdepartmental Division of Critical Care Medicine at the University of Toronto.

This dramatic effect prompted Dr. Slutsky and colleagues to investigate the mechanisms mediating end-organ damage triggered by ventilator-induced lung injury. Previously, “we showed that if you cause injury of the lung by ventilation, you actually can cause release of biochemical mediators, such as cytokines,” said Dr. Slutsky, also Vice President of Research at St. Michael’s Hospital in Toronto. Hypothetically, such biochemical signals might enter the circulation to wreak damage on other organs besides the lungs. He remarked, “That may be why patients with ARDS end up dying from multiple system organ failure.”

In the current study, Dr. Slutsky and colleagues established that blood-borne signals can trigger programmed cell death, or apoptosis, in tissues outside the lung. In addition, the researchers identified one of these signals as the soluble Fas ligand.

Although many studies had previously linked apoptosis with the soluble Fas ligand, this study was the first to demonstrate that “a mechanical stress like this could lead to [Fas ligand] release and lead to organ dysfunction,” Dr. Slutsky noted.

CHEMOKINES IMPLICATED

Twenty-four rabbits were intratracheally treated with hydrochloric acid to simulate ARDS. Twelve animals were subsequently given a noninjurious form of ventilation that included a tidal volume (VT) between 5 and 7 mL/kg and positive end-expiratory pressure (PEEP) between 9 and 12 cm H2O. Another 12 rabbits received a more injurious type of ventilation (VT, 15 to 17 mL/kg; PEEP, 0 to 3 cm H2O).

Eight hours after the start of ventilation, both groups of rabbits had increased levels of monocyte chemotactic protein 1, interleukin 8, and growth-related oncogene in plasma and pulmonary aspirates. However, the levels in the animals given noninjurious ventilation were significantly lower than those in the rabbits receiving injurious ventilation. Concentrations of chemokines like these have been shown to be increased in patients with ventilator-associated lung injury. Plasma levels of aspartate aminotransferase, lactate dehydrogenase, and creatinine were also increased in both groups, but they were markedly lower in the rabbits given noninjurious ventilation than in the other animals.

Evidence of apoptosis also varied markedly between the two groups, but the findings were tissue-specific. In the lungs, apoptosis rates were significantly higher in the rabbits given noninjurious ventilation. However, electron microscopy of type II alveolar epithelial cells revealed that these animals primarily had early membrane damage, whereas the rabbits given injurious ventilation had more significant injury and greater evidence of necrosis.

In epithelial cells of the intestinal villi and kidney tubules, the rabbits given injurious ventilation showed significantly higher apoptotic rates than did the other animals. Additionally, the rabbits given injurious ventilation had more intraepithelial lymphocytes and phagolysosomes in the small intestine surface epithelia and more pronounced bleb formation in tubular epithelia.

HUMORAL TRIGGERS

In vitro, 12-hour incubation with plasma taken from injuriously ventilated animals induced a markedly higher degree of apoptosis in cultured rabbit renal proximal tubular cells than did adding plasma from rabbits receiving noninjurious ventilation. It also yielded 80% more apoptotic cells than did control culture without plasma.

Soluble Fas ligand is known to induce alveolar epithelial apoptosis and lung damage in rabbits, as well as apoptosis in cultured human lung epithelia in vitro. Its role in plasma-induced augmentation of apoptosis in vitro was explored by introducing Fas:Ig, a fusion protein that binds the Fas ligand and which can block alveolar epithelial apoptosis and lung damage in vivo. Addition of Fas:Ig diminished the effect of the plasma from the injuriously ventilated rabbits: Compared with cells not treated with the fusion protein, Fas:Ig-treated cultured cells showed significantly less apoptosis.

FAS LIGAND IN ARDS PATIENTS

Levels of soluble Fas ligand are known to be elevated in bronchoalveolar lavage from ARDS patients. To further establish the clinical relevance of Fas ligand’s experimental activity, the research team compared soluble Fas ligand levels in plasma samples from ARDS patients given conventional ventilation with those in samples from patients treated with a protective ventilatory strategy. The patients given conventional ventilation had significantly higher levels after both 24 hours and 36 hours of mechanical ventilation. Furthermore, changes in soluble Fas ligand levels were significantly correlated with changes in creatinine concentration, suggesting Fas ligand’s involvement in renal dysfunction.

NEW THERAPEUTIC STRATEGIES

“In any patient with ARDS, you want to use the gentlest ventilatory strategy that can provide adequate gas exchange but also protect the lung. That’s ideal,” Dr. Slutsky emphasized. “The trouble is that in some patients, the lung injury is so bad, and the lung is so heterogeneously injured, that … a strategy that is protective in one region [may] cause more injury in another region.” For instance, high PEEP may maintain recruitment of one lung region, but may at the same time produce overdistension in another region, exacerbating injury. “Especially in those patients who have the most severe disease, maybe what we should be thinking about is developing a way to block the effect of various mediators that are released from the lung,” he suggested. Thus, one purpose of his research is “to try and find what’s causing the end-organ dysfunction and … aim therapy at blocking those molecules.”

Although Fas ligand likely contributed to apoptotic organ damage in these experiments, “I wouldn’t suggest that this is the one and only mechanism,” Dr. Slutsky admitted. “Mechanical ventilation does a lot of other things in terms of its effects on hemodynamics, hypoxia, low blood pressure …, and release of other things besides cytokines.” He noted that the search for agents to block such substances was an active area of study.

—Gale Jurasek

Reference
1. Imai Y, Parodo J, Kajikawa O, et al. Injurious mechanical ventilation and end-organ epithelial cell apoptosis and organ dysfunction in an experimental model of acute respiratory distress syndrome. JAMA. 2003;289:2104-2112.

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