Jim Lewis

Factors influencing efficacy of exogenous surfactant in acute lung injury.

Exogenous surfactant is currently being tested as a therapeutic modality for patients with acute respiratory distress syndrome (ARDS). Animal studies have shown that several factors may influence the efficacy of this treatment modality. These factors include the surfactant delivery method used (instillation vs. aerosolization), the timing of surfactant treatment over the course of injury, the specific surfactant preparation used, and the dose of surfactant administered. Each of these factors alone and together may influence the interaction of the exogenous surfactant with the hosts alveolar environment. This, in turn, may dictate how a specific patient responds to a particular surfactant treatment strategy. It is suggested that patients at an early stage of lung injury will benefit from aerosolized exogenous surfactant whereas large quantities of an instilled exogenous surfactant may be necessary at later stages of injury. Future studies will clarify how a specific surfactant treatment strategy should be chosen for an individual patient with ARDS.

Apolipoprotein E-Deficient Mice Are Susceptible to the Development of Acute Lung Injury

Background: Apolipoprotein E (apoE) has been shown to play a pivotal role in the development of cardiovascular disease, attributable to its function in lipid trafficking and immune modulating properties; however, its role in modulating inflammation in the setting of acute lung injury (ALI) is unknown. Objective: To determine whether apoE-deficient mice (apoE-/-) are more susceptible to ALI compared to wild-type (WT) animals. Methods: Two independent models of ALI were employed. Firstly, WT and apoE-/- mice were randomized to acid aspiration (50 μl of 0.1 N hydrochloric acid) followed by 4 h of mechanical ventilation. Secondly, WT and apoE-/- mice were randomized to 72 h of hyperoxia exposure or room air. Thereafter, the intrinsic responses of WT and apoE-/- mice were assessed using the isolated perfused mouse lung (IPML) setup. Finally, based on elevated levels of oxidized low-density lipoprotein (oxLDL) in apoE-/-, the effect of oxLDL on lung endothelial permeability and inflammation was assessed. Results: In both in vivo models, apoE-/- mice demonstrated greater increases in lung lavage protein levels, neutrophil counts, and cytokine expression (p < 0.05) compared to WT mice. Experiments utilizing the IPML setup demonstrated no differences in intrinsic lung responses to injury between apoE-/- and WT mice, suggesting the presence of a circulating factor as being responsible for the in vivo observations. Finally, the exposure of lung endothelial cells to oxLDL resulted in increased monolayer permeability and IL-6 release compared to native (nonoxidized) LDL. Conclusions: Our findings demonstrate a susceptibility of apoE-/- animals to ALI that may occur, in part, due to elevated levels of oxLDL.

Clinical characteristics of women with menstrual-linked asthma.

BACKGROUNDnMenstrual-linked asthma (MLA) is described in pre-menopausal women who experience a deterioration of asthma control peri-menstrually. The clinical characteristics of MLA remain incompletely defined. Our objective was to define the characteristics of MLA in a large female asthma cohort.nnnMETHODSnCross-sectional population survey. A comprehensive health questionnaire that included questions about MLA was administered to 1260 consecutive female asthma patients aged 12-55 years. Univariate and multivariate analyses were completed.nnnRESULTSnThe survey response rate was 43% (540/1260). The prevalence of self-reported MLA was 11% (60/540). Univariate: women with MLA compared to women without MLA had more urgent/emergent asthma-related healthcare visits/year, 6.18 (SD = ± 6.67) vs. 4.71 (SD = ± 5.91) (p=0.033), more emergency room visits, 1.50 (SD = ± 3.57) vs. 0.88 (SD = ± 2.27) (p=0.035), higher asthma-related absenteeism, 33/60 (57%) vs. 170/471 (37%) (p=0.003), and used almost twice the number of B(2)-agonist rescue doses/day, 1.13 (SD = ± 1.70) vs. 0.68 (SD = ± 1.32) (p=0.015). Multivariate: statistical significance was retained for absenteeism (p=0.016) and B(2)-agonist use (p=0.007) but lost for urgent healthcare visits (p=0.150) and emergency room visits (p=0.068).nnnCONCLUSIONSnSelf-reported MLA is common. Women with MLA in our population had a greater frequency of urgent healthcare visits, a higher rate of absenteeism, and used significantly more B(2)-agonist rescue than women without MLA. The association of increased health services use was not confirmed on multivariate analysis indicating that baseline characteristics associated with MLA in our population affected this outcome. MLA should be considered by healthcare providers when developing an asthma management plan.

A current and future perspective of exogenous surfactant therapy for acute respiratory distress syndrome

The acute respiratory distress syndrome (ARDS) is a disease defined by specific criteria of respiratory failure but caused by a variety of different insults. When designing exogenous surfactant treatment strategies for patients with ARDS, it is important first to characterize the lung injury and to optimize several factors that can influence the hosts response to this therapy. For example, in patients with established ARDS, large doses of a biophysically active surfactant delivered via instillation would be suitable. However, in patients with mild lung injury at risk of developing ARDS, a lower dose of a surfactant with anti-inflammatory properties delivered via aerosol may be optimal. If mechanical ventilation is required, using low tidal volume strategies with optimal positive end-respiratory pressure levels is suggested. We conclude that surfactant treatment strategies for ARDS should be tailored to the individual patient.

Potential Role for Pulmonary Surfactant in Lung Transplantation

Since its introduction in 1954 by Murray and colleagues, allotransplantation has greatly improved the quality, as well as the duration of life for those involved.1 The discovery of immunosuppressant drugs advanced long term efficacy of transplantation and led to a further improvement in the quality of life. Unfortunately, maximal potential benefits have never been achieved. As with a number of other organs, particularly kidneys, livers and hearts, there are lengthy waiting lists for suitable lungs. This lack of sufficient organs results, not only from the limited number of donors, but in part because many of the lungs available for transplant are judged unsuitable, due to edema, aspiration or contusion. The short period over which lungs remain clinically viable, presently 6–8 hours, also limits the availability of these organs. Furthermore, the practice of maintaining brain-damaged potential organ donors on respirators using high oxygen levels and vigorous mechanical ventilation contributes to the paucity of available lungs.

Effective in vivo treatment of acute lung injury with helical, amphipathic peptoid mimics of pulmonary surfactant proteins

Acute lung injury (ALI) leads to progressive loss of breathing capacity and hypoxemia, as well as pulmonary surfactant dysfunction. ALI’s pathogenesis and management are complex, and it is a significant cause of morbidity and mortality worldwide. Exogenous surfactant therapy, even for research purposes, is impractical for adults because of the high cost of current surfactant preparations. Prior in vitro work has shown that poly-N-substituted glycines (peptoids), in a biomimetic lipid mixture, emulate key biophysical activities of lung surfactant proteins B and C at the air-water interface. Here we report good in vivo efficacy of a peptoid-based surfactant, compared with extracted animal surfactant and a synthetic lipid formulation, in a rat model of lavage-induced ALI. Adult rats were subjected to whole-lung lavage followed by administration of surfactant formulations and monitoring of outcomes. Treatment with a surfactant protein C mimic formulation improved blood oxygenation, blood pH, shunt fraction, and peak inspiratory pressure to a greater degree than surfactant protein B mimic or combined formulations. All peptoid-enhanced treatment groups showed improved outcomes compared to synthetic lipids alone, and some formulations improved outcomes to a similar extent as animal-derived surfactant. Robust biophysical mimics of natural surfactant proteins may enable new medical research in ALI treatment.

Recombinant SP-C Based Surfactant Can Improve Lung Function in Saline Lavaged Sheep.

Clinical trials testing exogenous surfactant administration for the treatment of the Acute Respiratory Distress Syndrome (ARDS) have given variable results. Two factors contributing to the variable responses of this treatment are the specific exogenous surfactant preparation used and the method by which the surfactant is delivered to the injured lung. The current study investigated the potential of a new exogenous surfactant, recombinant SP-C based surfactant (rSP-C, Byk Gulden, Germany), to improve oxygenation in a large animal model of ARDS. The surfactant was delivered to the injured lungs by either tracheal instillation, bronchoscopic instillation or aerosolization. Lung injury was induced in adult sheep by repetitive saline lavage and subsequent mechanical ventilation for 1 hour. Two separate experiments were performed. In the first experiment, animals were then randomized into three different surfactant-instillation groups; 1) tracheal instillation of 100mgJkg; 2) tracheal installation of 25 mgJkg; 3) bronchoscopic installation of 25 mgJkg. The second experiment was performed to evaluate the efficacy of rSP-C surfactant when delivered as an aerosol. The aerosol rSP-C surfactant was delivered using a small catheter placed at the distal end of the endotracheal tube (Trudell Medical, London Ont) and was timed to deliver surfactant during inspiration only. This group of animals was compared to animals receiving air through a similar catheter. In both experiments the r-SP-C product was labeled with [14C]- dipalmitoyl phosphatidylcholine to assess the recovery and lobar distribution patterns of the exogenous surfactant. Blood gases were monitored at 30 min intervals for four hours after instillation or after the start of aerosolization. After the four hour monitoring period, animals were euthanized by an overdose of pentobarbitol and the lung were processed to examine the recovery and lobar distribution patterns of the exogenous material.