Early ReportDamage to surfactant-specific protein in acute respiratory distress syndrome
Introduction
Pulmonary surfactant is a mixture of phopholipids and surfactant-specific proteins, which reduces alveolar surface tension during respiration.1, 2 Specific proteins (SP) A, B, and C contribute to the biophysical functions of surfactant,3 and SP-A and SP-D also have antimicrobial properties.4, 5 The catastrophic consequences of major disturbance to surfactant are shown in the infant respiratory distress syndrome, which results from deficiency of surfactant at birth.1 Surfactant dysfunction also contributes substantially to pathogenesis in acute respiratory distress syndrome (ARDS).1 This severe form of adult lung injury develops in association with many serious conditions including sepsis, pneumonia, traumatic injury, and major surgery.2 Mortality exceeds 40%, and there is no effective therapy apart from mechanical ventilation and other supportive measures. Therapeutic surfactant is beneficial in infant respiratory distress syndrome1 and has potential for ARDS,2, 6 in which clinical trials have shown that artificial surfactant containing phospholipid without surfactant proteins is of no benefit7 but that the more effective preparations containing protein and phospholipid can improve gas exchange and reduce mortality.6 One outstanding question is whether antiinflammatory drugs are also needed to suppress products of activated neutrophils, which might damage surfactant.
The injury to the lungs in ARDS is caused by damage to the pulmonary vessels and alveoli, mediated in part by activated neutrophils,8 resulting in massive pulmonary oedema, neutrophilia, and surfactant dysfunction. The capacity of surfactant to lower surface tension is impaired in vivo in ARDS,2 owing to protein in oedema fluid inhibiting surfactant function,9 and to deficient production of surfactant.2 We sought evidence that direct damage to surfactant-specific proteins also contributes to surfactant dysfunction in ARDS because of their susceptibility to cleavage by proteases from activated neutrophils. This hypothesis is supported by several in-vitro observations. First, activated human neutrophils impair the function of surfactant in vitro by a mechanism that degrades SP-A, generating various bands of abnormal molecular weight.10 These abnormalities are inhibited by α1-antiprotease but not superoxide dismutase; thus they result from proteolysis and not from oxidant injury.10 Second, incubation of surfactant with neutrophil elastase in vitro also impairs the surface-tension-lowering capacity, and reduces the rate of surface absorption of surfactant; these changes are associated not only with proteolytic cleavage of SP-A, but also with damage to SP-B and SP-C.11 Third, all three of these surfactant-specific proteins can be cleaved by neutrophil elastase in vitro.12
In normal lungs, the inhibitor α1-antiprotease inactivates free elastase. However, bronchoalveolar lavage samples from patients with ARDS contain raised amounts of active neutrophil elastase13, 14, 15 and decreased antiprotease activity,16 indicating that proteolytic damage may occur as a result of imbalance between protease and inhibitor. Elastase inhibitor can attenuate lipopolysaccharide-induced acute lung injury.17 The availability of recombinant α1-antiprotease and other protease inhibitors for clinical trials in human beings now makes antiprotease therapy feasible.
We studied surfactant from patients with ARDS and healthy controls, looking for damage to SP-A.
Section snippets
Methods
We selected for investigation 18 patients with ARDS (nine male, nine female; median age 57 [range 16–74] years; seven never-smokers, five current smokers, six ex-smokers; six survivors, 12 non-survivors) from whom sufficient bronchoalveolar lavage fluid was recovered. All met the diagnostic criteria of the American-European Consensus,18 and all had severe lung injury according to the Murray lung-injury score.19 The study protocol was approved by the ethics committee of the Royal Brompton
Results
The six surviving and 12 non-surviving patients were of similar age (table) and had had a similar duration of mechanical ventilation at the time of bronchoalveolar lavage (median 8 days for both). All 18 patients had higher than normal numbers of neutrophils in their bronchoalveolar lavage samples (median percentage count 87·4%; number 20·5×104/mL). Under reducing conditions, the purified SP-A from the patient with alveolar lipoproteinosis separated into two major protein bands (Figure 1, A): a
Discussion
The lungs of patients with ARDS contain higher than normal numbers of activated neutrophils8 and amounts of free elastase released from the neutrophils.13, 14, 15 The incomplete inactivation of elastase seems to be the result of damage to its main inhibitor, α1- antiprotease.14, 16 On the basis of these observations, others have proposed that the specific proteins of the pulmonary surfactant system might be at risk of cleavage by the active elastase in the lungs of patients with ARDS. This
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