Vivien Chan

Multiple β1 Integrins Mediate Enhancement of Human Airway Smooth Muscle Cytokine Secretion by Fibronectin and Type I Collagen

Altered airway smooth muscle (ASM) function and enrichment of the extracellular matrix (ECM) with interstitial collagen and fibronectin are major pathological features of airway remodeling in asthma. We have previously shown that these ECM components confer enhanced ASM proliferation in vitro, but their action on its newly characterized secretory function is unknown. Here, we examined the effects of fibronectin and collagen types I, III, and V on IL-1β-dependent secretory responses of human ASM cells, and characterized the involvement of specific integrins. Cytokine production (eotaxin, RANTES, and GM-CSF) was evaluated by ELISA, RT-PCR, and flow cytometry. Function-blocking integrin mAbs and RGD (Arg-Gly-Asp)-blocking peptides were used to identify integrin involvement. IL-1β-dependent release of eotaxin, RANTES, and GM-CSF was enhanced by fibronectin and by fibrillar and monomeric type I collagen, with similar changes in mRNA abundance. Collagen types III and V had no effect on eotaxin or RANTES release but did modulate GM-CSF. Analogous changes in intracellular cytokine accumulation were found, but in <25% of the total ASM cell population. Function-blocking Ab and RGD peptide studies revealed that α2β1, α5β1, αvβ1, and αvβ3 integrins were required for up-regulation of IL-1β-dependent ASM secretory responses by fibronectin, while α2β1 was an important transducer for type I collagen. Thus, fibronectin and type I collagen enhance IL-1β-dependent ASM secretory responses through a β1 integrin-dependent mechanism. Enhancement of cytokine release from ASM by these ECM components may contribute to airway wall inflammation and remodeling in asthma.

Airway pressure triggered ventilation for preterm neonates

The usefulness of airway pressure triggered ventilation for the preterm newborn has been assessed using a new patient triggered valveless ventilator, the SLE 2000 infant ventilator (SLE 2000). This ventilator performs well at fast rates with no inadvertent positive end expiratory pressure (PEEP) even at rates of 150 breaths per minute (bpm). The ventilator is triggered by a change in airway pressure equal to or exceeding 0.5 cmH2O. If the infant fails to achieve the change in airway pressure which will trigger the ventilator the infant is ventilated at the back-up rate which is predetermined in conventional mode prior to commencing PTV. Infants were ventilated for one hour on a conventional neonatal ventilator, then for one hour on the SLE 2000 in conventional mode without changing the ventilator settings and finally for one hour on the SLE 2000 in patient triggered mode. Arterial blood gases were checked at the end of each hour. During patient triggered ventilation (PTV) the peak pressure, inspiratory time and inspired oxygen concentration were the same as those used during conventional mode. Simultaneous recordings were made of flow, volume, ventilator and oesophageal pressure change, from this recording the trigger delay during PTV was calculated. The trigger delay, being the time lag from the start of spontaneous inspiration, indicated by the negative deflection in the oesophageal pressure trace, and the onset of the ventilator breath. Thirteen infants were included in the study, median gestational age 32 weeks (range 25-35) and birthweight 1640 g (range 838-3038). All were being ventilated for respiratory distress syndrome (RDS) and were 4 days of age.(ABSTRACT TRUNCATED AT 250 WORDS)

Vitamin A status in preterm and term infants at birth.

Vitamin A status was determined in infants born at term or prematurely to assess if vitamin A levels at birth were related to gestational age. Vitamin A levels were measured in cord blood samples from 13 infants born at term and in blood samples obtained within two hours of birth in 26 preterm infants (median gestational age 31 weeks, range 27-35). None of the preterm infants developed chronic lung disease. The vitamin A levels of the term infants (median 0.71 mumol/l, range 0.34 to 1.27) were significantly higher than those of infants born preterm (median 0.35 mumol/l, range 0.12 to 1.22), p < 0.01. Vitamin A levels correlated significantly with gestational age (vitamin A level = 0.024 gestational age (weeks) -0.23, r = 0.39, p < 0.02. We thus conclude that gestational age must be taken into account when interpreting vitamin A levels.

The effect of frequency on carbon dioxide levels during high frequency oscillation.

The aim of this study was to assess if, during high frequency oscillation (HFO), a frequency of 10 or 15 Hz was associated with lower carbon dioxide levels. Twelve infants were recruited, median gestational age 27 weeks. All infants were studied at both frequencies, applied in random order and the carbon dioxide level checked after 30 minutes on each frequency. Carbon dioxide levels were lower in 10 of the 12 infants at 10 compared to 15 Hz (p < 0.004) and, in the study population, overall were significantly lower at 10 Hz (p < 0.05). The difference in paCO2 levels at the two frequencies, however, was small, thus these results suggest the clinician should rely primarily on changes in oscillatory amplitude, rather than frequency, to effect changes in carbon dioxide levels.

Antenatal and postnatal treatment of pleural effusion and extra-lobar pulmonary sequestration

An infant is reported who was identified antenatally to have an extralobar sequestration and a pleural effusion. Chronic drainage of the effusion was achieved by placement of a pleuroamniotic shunt. After delivery the infant underwent several thoracocenteses and then definitive surgery to remove an extralobar sequestration. The postnatal course was documented by lung function measurements.

Vitamin A levels at birth of high risk preterm infants

Vitamin A levels were measured shortly after birth in preterm infants at high risk of developing chronic lung disease (CLD). Eleven infants, median gestational age 24 weeks, developed CLD. Their results were compared to 11 infants who, although they required mechanical ventilation for at least 48 hours, did not develop CLD. The median gestational age of this latter group was 30 weeks (range 27-35). The median vitamin A level of the infants who developed CLD was 0.62 umol/l (range 0.41-0.95), which was significantly higher than the median level of the infants who did not develop CLD, which was 0.36 umol/l (range 0.13-0.89). We conclude preterm infants who develop CLD are not predisposed to develop that complication by low vitamin A levels at birth.

Vitamin A levels and feeding practice in neonates with and without chronic lung disease

Infants with chronic lung disease (CLD) have been demonstrated to have low vitamin A levels. The aim of this study was to assess factors which influenced this association. Vitamin A levels of infants born at less than 32 weeks gestational age with and without CLD were determined and related to feeding practice. The infants with CLD had statistically significantly lower vitamin A levels on days 21 to 30 and days 31 to 40. From day 11 onwards, the median Vitamin A levels were less than 60% of the minimum acceptable level for a healthy child or adult. Infants with CLD required significantly longer mechanical ventilation and parenteral nutrition than controls and there was a significant positive correlation between duration of mechanical ventilation and parenteral nutrition (r = 0.83). Infants with CLD received significantly less vitamin A supplementation than the infants without CLD. Our results thus suggest that feeding practice explains the association of CLD and vitamin A deficiency in preterm infants.

The performance of a new valveless ventilator at rates of up to 250 bpm

The efficacy of a new ventilator, incorporating a valveless pneumatic exhalation circuit, at rates of up to 250 bpm was first assessed in the laboratory. Using this ventilator the effect of fast rate ventilation on blood gases of infants with acute respiratory distress was then examined. Infants were studied at three rates: 60, 125 and 250 bpm. Peak inflating and positive end expiratory pressure, inspiratory: expiratory ratio and inspired oxygen were kept constant. The laboratory study demonstrated that as ventilator rate was increased the delivered volume fell, but even at 250 bpm the delivered volume was 7 ml. In the clinical study, oxygenation at 250 bpm was not significantly different from that at 60 bpm, but significantly lower than at 125 pbm. Carbon dioxide levels were significantly lower at 250 bpm that at 60 bpm, but did not differ significantly from that at 125 bpm. We conclude increasing ventilator rate from 125 to 250 bpm is not advantageous for infants ventilated for acute respiratory distress.

276 INFLUENCE OF LUNG FUNCTION AND REFLEX ACTIVITY ON THE SUCCESS OF PATIENT TRIGGERED VENTILATION

During patient triggered ventilation (PTV) each of the infants respiratory efforts will trigger a positive pressure inflation, providing that the respiratory effort is of sufficient magnitude to exceed the critical trigger level. It is likely therefore that the nature of the infants lung function and respiratory reflex activity will influence the success of PTV. The aim of this study was to test that hypothesis. 20 premature infants (median gestational age 29 weeks) in the recovery stage of respiratory distress were studied at a median postnatal age of 2.5 days. Lung function was assessed by measurement of compliance using a single breath technique. Reflex activity was assessed by measurement of the strength of the Hering Breuer reflex, indicated by the degree of prolongation of expiration following end inspiratory occlusion. PTV was considered to have failed if the infant became apnoeic or required an increased level of respiratory support. PTV failed ultimately in 6 infants, compliance of the respiratory system of those 6 infants did not differ significantly from the rest of the cohon, but the Hering Breuer reflex was significantly weaker (p<0.01). Although the infants in whom PTV failed compared to those in whom it succeeded were significantly more immature and of lower birthweight (p < 0.01), multiple regression analysis demonstrated that reflex activity was independently associated with PTV failure after accounting for gestational age. birthweight and compliance. We conclude that failure of PTV is more likely in immature infants who have a weak Hering Breuer reflex.