Gastroesophageal reflux and pulmonary fibrosis in scleroderma: a study using pH-impedance monitoring

RATIONALE: Interstitial lung disease (ILD) in patients with systemic sclerosis (SSc) is associated with increased morbidity and mortality. Gastroesophageal reflux (GER) is considered a contributing factor in the pathogenesis of ILD. OBJECTIVES: To characterize GER (acid and nonacid) in patients with SSc with and without ILD. METHODS: Patients with SSc underwent pulmonary high-resolution computer tomography (HRCT) scan and 24-hour impedance-pH monitoring off-proton pump inhibitor therapy. The presence of pulmonary fibrosis was assessed using validated HRCT-scores. Reflux monitoring parameters included number of acid and nonacid reflux episodes, proximal migration of the refluxate, and distal esophageal acid exposure. Unless otherwise specified, data are presented as median (25th-75th percentile). MEASUREMENTS AND MAIN RESULTS: Forty consecutive patients with SSc (35 female; mean age, 53 yr; range, 24-71; 15 patients with diffuse and 25 with limited SSc) were investigated; 18 (45%) patients with SSc had pulmonary fibrosis (HRCT score >or= 7). Patients with SSc with ILD had higher (P < 0.01) esophageal acid exposure (10.3 [7.5-15] vs. 5.2 [1.5-11]), higher (P < 0.01) number of acid (41 [31-58] vs. 19 [10-23]) and nonacid (25 [20-35] vs. 17 [11-19]) reflux episodes, and higher (P < 0.01) number of reflux episodes reaching the proximal esophagus (42.5 [31-54] vs. 15 [8-22]) compared with patients with SSc with normal HRCT scores. Pulmonary fibrosis scores (HRCT score) correlated well with the number of reflux episodes in the distal (r(2) = 0.637) and proximal (r(2) = 0.644) esophagus. CONCLUSIONS: Patients with SSc with ILD have more severe reflux (i.e., more reflux episodes and more reflux reaching the proximal esophagus). Whether or not the development of ILD in patients with SSc can be prevented by reflux-reducing treatments needs to be investigated.

Catch-up alveolarization in ex-preterm children: evidence from (3)He magnetic resonance

RATIONALE Histologic data from fatal cases suggest that extreme prematurity results in persisting alveolar damage. However, there is new evidence that human alveolarization might continue throughout childhood and could contribute to alveolar repair. OBJECTIVES To examine whether alveolar damage in extreme-preterm survivors persists into late childhood, we compared alveolar dimensions between schoolchildren born term and preterm, using hyperpolarized helium-3 magnetic resonance. METHODS We recruited schoolchildren aged 10-14 years stratified by gestational age at birth (weeks) to four groups: (1) term-born (37-42 wk; n = 61); (2) mild preterm (32-36 wk; n = 21); (3) extreme preterm (<32 wk, not oxygen dependent at 4 wk; n = 19); and (4) extreme preterm with chronic lung disease (<32 wk and oxygen dependent beyond 4 wk; n = 18). We measured lung function using spirometry and plethysmography. Apparent diffusion coefficient, a surrogate for average alveolar dimensions, was measured by helium-3 magnetic resonance. MEASUREMENTS AND MAIN RESULTS The two extreme preterm groups had a lower FEV1 (P = 0.017) compared with term-born and mild preterm children. Apparent diffusion coefficient was 0.092 cm(2)/second (95% confidence interval, 0.089-0.095) in the term group. Corresponding values were 0.096 (0.091-0.101), 0.090 (0085-0.095), and 0.089 (0.083-0.094) in the mild preterm and two extreme preterm groups, respectively, implying comparable alveolar dimensions across all groups. Results did not change after controlling for anthropometric variables and potential confounders. CONCLUSIONS Alveolar size at school age was similar in survivors of extreme prematurity and term-born children. Because extreme preterm birth is associated with deranged alveolar structure in infancy, the most likely explanation for our finding is catch-up alveolarization.

Volumetric capnography in infants with bronchopulmonary dysplasia.

OBJECTIVES To assess the feasibility of using volumetric capnography in spontaneously breathing small infants and its ability to discriminate between infants with and without bronchopulmonary dysplasia (BPD). STUDY DESIGN Lung function variables for 231 infants (102 term, 52 healthy preterm, 77 BPD), matched for post-conceptional age of 44 weeks, were collected. BPD was defined as supplemental oxygen requirement at 36 weeks post-menstrual age. Tidal breath-by-breath volume capnograms were obtained by mainstream capnography. The capnographic slope of phase II (SII) and slope of phase III (SIII) were calculated and compared between study groups. The effect of BPD, tidal volume (VT), respiratory rate (RR), and prematurity on the magnitude of the slopes was assessed. RESULTS SII was steeper in infants with BPD (100 ± 28/L) compared with healthy preterm (88 ± 22/L; P = .007) and term infants (79 ± 18/L; P < .001), but this finding was attributed to differences in VT, RR, and gestational age. SIII was steeper in the BPD group (26.8 ± 14.1/L) compared with healthy preterm (16.2 ± 6.2/L; P < .001) and term controls (14.8 ± 5.4/L; P < .001). BPD was a significant predictor of SIII independently of VT, RR, and gestational age. The ability of SIII to discriminate between BPD and controls was significantly higher compared with lung clearance index (area under the curve 0.83 vs 0.56; P < .001). CONCLUSIONS Volumetric capnography may provide valuable information regarding functional lung alterations related to BPD and might be considered as an alternative to more involved lung function techniques for monitoring chronic lung disease during early infancy.

Health care index score and risk of death following tuberculosis diagnosis in HIV-positive patients

OBJECTIVES: To assess health care utilisation for patients co-infected with TB and HIV (TB-HIV), and to develop a weighted health care index (HCI) score based on commonly used interventions and compare it with patient outcome. METHODS: A total of 1061 HIV patients diagnosed with TB in four regions, Central/Northern, Southern and Eastern Europe and Argentina, between January 2004 and December 2006 were enrolled in the TB-HIV study. A weighted HCI score (range 0–5), based on independent prognostic factors identified in multivariable Cox models and the final score, included performance of TB drug susceptibility testing (DST), an initial TB regimen containing a rifamycin, isoniazid and pyrazinamide, and start of combination antiretroviral treatment (cART). RESULTS: The mean HCI score was highest in Central/Northern Europe (3.2, 95%CI 3.1–3.3) and lowest in Eastern Europe (1.6, 95%CI 1.5–1.7). The cumulative probability of death 1 year after TB diagnosis decreased from 39% (95%CI 31–48) among patients with an HCI score of 0, to 9% (95%CI 6–13) among those with a score of ≥4. In an adjusted Cox model, a 1-unit increase in the HCI score was associated with 27% reduced mortality (relative hazard 0.73, 95%CI 0.64–0.84). CONCLUSIONS: Our results suggest that DST, standard anti-tuberculosis treatment and early cART may improve outcome for TB-HIV patients. The proposed HCI score provides a tool for future research and monitoring of the management of TB-HIV patients. The highest HCI score may serve as a benchmark to assess TB-HIV management, encouraging continuous health care improvement.

The Role of IL-6 in Adenosine-Mediated Pulmonary Fibrosis

Adenosine is a purinergic signaling molecule that regulates various aspects of inflammation and has been implicated in the pathogenesis of chronic lung diseases. Previous studies have demonstrated that adenosine up-regulates IL-6 production through the engagement of the A2B adenosine receptor in various cell types, including alveolar macrophages. IL-6 is elevated in mouse models and humans with chronic lung disease, suggesting a potential role in disease progression. Furthermore, chronic elevation of adenosine in the lungs of adenosine deaminase deficient (Ada-/-) mice leads to the development of pulmonary inflammation, alveolar destruction, and fibrosis, in conjunction with IL-6 elevation. Thus, it was hypothesized that IL-6 contributes to pulmonary inflammation and fibrosis in this model. To test this hypothesis, Ada/IL-6 double knockout mice (Ada/IL-6-/-) were generated to assess the consequences of genetically removing IL-6 on adenosine-dependent pulmonary injury. Ada/IL-6-/- mice exhibited a significant reduction in inflammation, alveolar destruction, and pulmonary fibrosis. Next, Ada-/- mice were treated systematically with IL-6 neutralizing antibodies to test the efficacy of blocking IL-6 on chronic lung disease. These treatments were associated with decreased pulmonary inflammation, alveolar destruction, and fibrosis. To determine the role of IL-6 in a second model of pulmonary fibrosis, wild type mice and IL-6-/- mice were subjected to intraperitoneal injections of bleomycin twice a week for four weeks. Results demonstrated that IL-6-/- mice developed reduced pulmonary fibrosis. To examine a therapeutic approach in this model, wild type mice exposed to bleomycin were treated with IL-6 neutralizing antibodies. Similar results were observed as with Ada-/- mice, namely diminished pulmonary inflammation and fibrosis. In both models, elevations in IL-6 were associated with increased phosphorylated STAT-3 in the nuclei of numerous cell types in the airways, including type II alveolar epithelial cells (AEC). Genetic removal and neutralization of IL-6 in both models was associated with decreased STAT-3 activation in type II AEC. The mechanism of activation in these cells that lack the membrane bound IL-6Ra suggests IL-6 trans-signaling may play a role in regulating fibrosis. Characterization of this mechanism demonstrated that the soluble IL-6Ra (sIL-6Ra) is upregulated in both models during chronic conditions. In vitro studies in MLE-12 alveolar epithelial cells confirmed that IL-6, in combination with the sIL-6Ra, activates STAT-3 and TWIST in association with enhancement of epithelial-to-mesenchymal transition, which can contribute to fibrosis. Similarly, patients with idiopathic pulmonary fibrosis demonstrated a similar pattern of increased IL-6 expression, STAT-3 activation, and sIL-6Ra increases. These findings demonstrate that adenosine-dependent elevations in IL-6 contribute to the development and progression of pulmonary inflammation and fibrosis. The implications from these studies are that adenosine and/or IL-6 neutralizing agents represent novel therapeutic targets for the treatment of pulmonary disorders where fibrosis is a detrimental component.

Comparisons of Mortality and Pre-discharge Respiratory Outcomes in Small-for-gestational-age and Appropriate-for-gestational-age Premature Infants.

BACKGROUND: There are differences in the literature regarding outcomes of premature small-for-gestational-age (SGA) and appropriate-for gestational-age (AGA) infants, possibly due to failure to take into account gestational age at birth. OBJECTIVE: To compare mortality and respiratory morbidity of SGA and AGA premature newborn infants. DESIGN/METHODS: A retrospective study was done of the 2,487 infants born without congenital anomalies at RESULTS: Controlling for GA, premature SGA infants were at a higher risk for mortality (Odds ratio 3.1, P = 0.001) and at lower risk of respiratory distress syndrome (OR = 0.71, p = 0.02) than AGA infants. However multivariate logistic regression modeling found that the odds of having respiratory distress syndrome (RDS) varied between SGA and AGA infants by GA. There was no change in RDS risk in SGA infants at GA 32 wk (OR = 0.41, 95% CI 0.27 - 0.63; p < 0.01). After controlling for GA, SGA infants were observed to be at a significantly higher risk for developing chronic lung disease as compared to AGA infants (OR = 2.2, 95% CI = 1.2 - 3.9, P = 0.01). There was no significant difference between SGA and AGA infants in total days on ventilator. Among infants who survived, mean length of hospital stay was significantly higher in SGA infants born between 26-36 wks GA than AGA infants. CONCLUSIONS: Premature SGA infants have significantly higher mortality, significantly higher risk of developing chronic lung disease and longer hospital stay as compared to premature AGA infants. Even the reduced risk of RDS in infants born at >/=32 wk GA, (conferred possibly by intra-uterine stress leading to accelerated lung maturation) appears to be of transient effect and is counterbalanced by adverse effects of poor intrauterine growth on long term pulmonary outcomes such as chronic lung disease.

Detection and management of drug-resistant tuberculosis in HIV-infected patients in lower-income countries.

SETTING Drug resistance threatens tuberculosis (TB) control, particularly among human immunodeficiency virus (HIV) infected persons. OBJECTIVE To describe practices in the prevention and management of drug-resistant TB under antiretroviral therapy (ART) programs in lower-income countries. DESIGN We used online questionnaires to collect program-level data on 47 ART programs in Southern Africa (n = 14), East Africa (n = 8), West Africa (n = 7), Central Africa (n = 5), Latin America (n = 7) and the Asia-Pacific (n = 6 programs) in 2012. Patient-level data were collected on 1002 adult TB patients seen at 40 of the participating ART programs. RESULTS Phenotypic drug susceptibility testing (DST) was available in 36 (77%) ART programs, but was only used for 22% of all TB patients. Molecular DST was available in 33 (70%) programs and was used in 23% of all TB patients. Twenty ART programs (43%) provided directly observed therapy (DOT) during the entire course of treatment, 16 (34%) during the intensive phase only, and 11 (23%) did not follow DOT. Fourteen (30%) ART programs reported no access to second-line anti-tuberculosis regimens; 18 (38%) reported TB drug shortages. CONCLUSIONS Capacity to diagnose and treat drug-resistant TB was limited across ART programs in lower-income countries. DOT was not always implemented and drug supplies were regularly interrupted, which may contribute to the global emergence of drug resistance.

Alternative outcomes for the multiple breath washout in children with CF

BACKGROUND The lung clearance index (LCI) measured by multiple-breath washout (MBW) has been proposed as an outcome for clinical trials; however, MBW is time consuming and LCI can be affected by breathing pattern. We aimed to evaluate moment ratios and abbreviated LCI in school-aged children with mild-to-moderate CF lung disease. METHODS Using existing data from three studies we assessed the sensitivity of moment ratios and abbreviated LCIs to (i) detect mild-to-moderate CF lung disease and (ii) detect treatment effects after 4weeks of hypertonic saline or dornase alfa inhalation. MBW was measured by respiratory mass spectrometry using 4% "sulphur hexafluoride as a tracer gas. RESULTS Compared to the traditional LCI, moment ratios and abbreviated LCIs were similarly sensitive to detect CF lung disease. Moment ratios consistently demonstrated treatment effects, whereas abbreviated LCIs were less sensitive. CONCLUSIONS Both moment ratios and abbreviated LCI are suitable to differentiate health from disease. Sensitivity is decreased for abbreviated LCIs in interventional studies in mild CF lung disease.

Toxicity of aged gasoline exhaust particles to normal and diseased airway epithelia

Particulate matter (PM) pollution is a leading cause of premature death, particularly in those with pre-existing lung disease. A causative link between particle properties and adverse health effects remains unestablished mainly due to complex and variable physico-chemical PM parameters. Controlled laboratory experiments are required. Generating atmospherically realistic Aerosols and performing cell-exposure studies at relevant particle-doses are challenging. Here we examine gasoline-exhaust particle toxicity from a Euro-5 passenger car in a uniquely realistic exposure scenario, combining a smog chamber simulating atmospheric ageing, an aerosol enrichment System varying particle number concentration independent of particle chemistry, and an aerosol Deposition chamber physiologically delivering particles on air-liquid interface (ALI) cultures reproducing normal and susceptible health status. Gasoline-exhaust is an important PM source with largely unknown health effects. We investigated acute responses of fully-differentiated normal, distressed (antibiotics treated) normal, and cystic fibrosis human bronchial epithelia (HBE), and a proliferating, single-cell type bronchial epithelial cell-line (BEAS-2B). We show that a single, short-term exposure to realistic doses of atmospherically-aged gasoline-exhaust particles impairs epithelial key-defence mechanisms, rendering it more vulnerable to subsequent hazards. We establish dose-response curves at realistic particle-concentration levels. Significant differences between cell models suggest the use of fully differentiated HBE is most appropriate in future toxicity studies.

ERS statement on the multidisciplinary respiratory management of ataxia telangiectasia.

Ataxia telangiectasia (A-T) is a rare, progressive, multisystem disease that has a large number of complex and diverse manifestations which vary with age. Patients with A-T die prematurely with the leading causes of death being respiratory diseases and cancer. Respiratory manifestations include immune dysfunction leading to recurrent upper and lower respiratory infections; aspiration resulting from dysfunctional swallowing due to neurodegenerative deficits; inefficient cough; and interstitial lung disease/pulmonary fibrosis. Malnutrition is a significant comorbidity. The increased radiosensitivity and increased risk of cancer should be borne in mind when requesting radiological investigations. Aggressive proactive monitoring and treatment of these various aspects of lung disease under multidisciplinary expertise in the experience of national multidisciplinary clinics internationally forms the basis of this statement on the management of lung disease in A-T. Neurological management is outwith the scope of this document.

Idiopathic pulmonary fibrosis: the turning point is now!

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease with poor survival. Recent studies have improved understanding of IPF and new discoveries have led to novel treatment options, which now have become available for patients. In face of the newly available therapies we present an update on the pathophysiology and epidemiology of IPF. We discuss the typical clinical findings and elaborate diagnostic procedures according to current guidelines and our daily practice approach. The role of biomarkers will briefly be outlined. Finally, we discuss novel antifibrotic treatment options for IPF (pirfenidone, nintedanib) and the management of patients regarding to comorbidities and complications. Both pirfenidone and nintedanib were shown to reduce the progression of IPF and therefore represent novel therapeutic strategies in this so far untreatable chronic lung disease.

Long-term data from the Swiss pulmonary hypertension registry.

BACKGROUND Registries are important for real-life epidemiology on different pulmonary hypertension (PH) groups. OBJECTIVE To provide long-term data of the Swiss PH registry of 1998-2012. METHODS PH patients have been classified into 5 groups and registered upon written informed consent at 5 university and 8 associated hospitals since 1998. New York Heart Association (NYHA) class, 6-min walk distance, hemodynamics and therapy were registered at baseline. Patients were regularly followed, and therapy and events (death, transplantation, endarterectomy or loss to follow-up) registered. The data were stratified according to the time of diagnosis into prevalent before 2000 and incident during 2000-2004, 2005-2008 and 2009-2012. RESULTS From 996 (53% female) PH patients, 549 had pulmonary arterial hypertension (PAH), 36 PH due to left heart disease, 127 due to lung disease, 249 to chronic thromboembolic PH (CTEPH) and 35 to miscellaneous PH. Age and BMI significantly increased over time, whereas hemodynamic severity decreased. Overall, event-free survival was 84, 72, 64 and 58% for the years 1-4 and similar for time periods since 2000, but better during the more recent periods for PAH and CTEPH. Of all PAH cases, 89% had target medical therapy and 43% combination therapy. Of CTEPH patients, 14 and 2% underwent pulmonary endarterectomy or transplantation, respectively; 87% were treated with PAH target therapy. CONCLUSION Since 2000, the incident Swiss PH patients registered were older, hemodynamically better and mostly treated with PAH target therapies. Survival has been better for PAH and CTEPH diagnosed since 2008 compared with earlier diagnosis or other classifications.

Impact of Software Settings on Multiple-Breath Washout Outcomes

BACKGROUND AND OBJECTIVES Multiple-breath washout (MBW) is an attractive test to assess ventilation inhomogeneity, a marker of peripheral lung disease. Standardization of MBW is hampered as little data exists on possible measurement bias. We aimed to identify potential sources of measurement bias based on MBW software settings. METHODS We used unprocessed data from nitrogen (N2) MBW (Exhalyzer D, Eco Medics AG) applied in 30 children aged 5-18 years: 10 with CF, 10 formerly preterm, and 10 healthy controls. This setup calculates the tracer gas N2 mainly from measured O2 and CO2concentrations. The following software settings for MBW signal processing were changed by at least 5 units or >10% in both directions or completely switched off: (i) environmental conditions, (ii) apparatus dead space, (iii) O2 and CO2 signal correction, and (iv) signal alignment (delay time). Primary outcome was the change in lung clearance index (LCI) compared to LCI calculated with the settings as recommended. A change in LCI exceeding 10% was considered relevant. RESULTS Changes in both environmental and dead space settings resulted in uniform but modest LCI changes and exceeded >10% in only two measurements. Changes in signal alignment and O2 signal correction had the most relevant impact on LCI. Decrease of O2 delay time by 40 ms (7%) lead to a mean LCI increase of 12%, with >10% LCI change in 60% of the children. Increase of O2 delay time by 40 ms resulted in mean LCI decrease of 9% with LCI changing >10% in 43% of the children. CONCLUSIONS Accurate LCI results depend crucially on signal processing settings in MBW software. Especially correct signal delay times are possible sources of incorrect LCI measurements. Algorithms of signal processing and signal alignment should thus be optimized to avoid susceptibility of MBW measurements to this significant measurement bias.

Accuracy of tidal breathing measurement of FloRight compared to an ultrasonic flowmeter in infants.

INTRODUCTION Monitoring breathing pattern is especially relevant in infants with lung disease. Recently, a vest-based inductive plethysmograph system (FloRight®) has been developed for tidal breathing measurement in infants. We investigated the accuracy of tidal breathing flow volume loop (TBFVL) measurements in healthy term-born infants and infants with lung disease by the vest-based system in comparison to an ultrasonic flowmeter (USFM) with a face mask. We also investigated whether the system discriminates between healthy infants and those with lung disease. METHODS Floright® measures changes in thoracoabdominal volume during tidal breathing through magnetic field changes generated by current-carrying conductor coils in an elastic vest. Simultaneous TBFVL measurements by the vest-based system and the USFM were performed at 44 weeks corrected postmenstrual age during quiet unsedated sleep. TBFVL parameters derived by both techniques and within both groups were compared. RESULTS We included 19 healthy infants and 18 infants with lung disease. Tidal volume per body weight derived by the vest-based system was significantly lower with a mean difference (95% CI) of -1.33 ml/kg (-1.73; -0.92), P < 0.001. Respiratory rate and ratio of time to peak tidal expiratory flow over total expiratory time (tPTEF/tE) did not differ between the two techniques. Both systems were able to discriminate between healthy infants and those with lung disease using tPTEF/tE. CONCLUSION FloRight® accurately measures time indices and may discriminate between healthy infants and those with lung disease, but demonstrates differences in tidal volume measurements. It may be better suited to monitor breathing pattern than for TBFVL measurements.

Gene expression profile in newborn rat lungs after two days of recovery of mechanical ventilation.

BACKGROUND Preterm infants having immature lungs often require respiratory support, potentially leading to bronchopulmonary dysplasia (BPD). Conventional BPD rodent models based on mechanical ventilation (MV) present outcome measured at the end of the ventilation period. A reversible intubation and ventilation model in newborn rats recently allowed discovering that different sets of genes modified their expression related to time after MV. In a newborn rat model, the expression profile 48 h after MV was analyzed with gene arrays to detect potentially interesting candidates with an impact on BPD development. METHODS Rat pups were injected P4-5 with 2 mg/kg lipopolysaccharide (LPS). One day later, MV with 21 or 60% oxygen was applied during 6 h. Animals were sacrified 48 h after end of ventilation. Affymetrix gene arrays assessed the total gene expression profile in lung tissue. RESULTS In fully treated animals (LPS + MV + 60% O(2)) vs. controls, 271 genes changed expression significantly. All modified genes could be classified in six pathways: tissue remodeling/wound repair, immune system and inflammatory response, hematopoiesis, vasodilatation, and oxidative stress. Major alterations were found in the MMP and complement system. CONCLUSION MMPs and complement factors play a central role in several of the pathways identified and may represent interesting targets for BPD treatment/prevention.Bronchopulmonary dysplasia (BPD) is a chronic lung disease occurring in ~30% of preterm infants born less than 30 wk of gestation (1). Its main risk factors include lung immaturity due to preterm delivery, mechanical ventilation (MV), oxygen toxicity, chorioamnionitis, and sepsis. The main feature is an arrest of alveolar and capillary formation (2). Models trying to decipher genes involved in the pathophysiology of BPD are mainly based on MV and oxygen application to young mammals with immature lungs of different species (3). In newborn rodent models, analyses of lung structure and gene and protein expression are performed for practical reasons directly at the end of MV (4,5,6). However, later appearing changes of gene expression might also have an impact on lung development and the evolution towards BPD and cannot be discovered by such models. Recently, we developed a newborn rat model of MV using an atraumatic (orotracheal) intubation technique that allows the weaning of the newborn animal off anesthesia and MV, the extubation to spontaneous breathing, and therefore allows the evaluation of effects of MV after a ventilation-free period of recovery (7). Indeed, applying this concept of atraumatic intubation by direct laryngoscopy, we recently were able to show significant differences between gene expression changes appearing directly after MV compared to those measured after a ventilation-free interval of 48 h. Immediately after MV, inflammation-related genes showed a transitory modified expression, while another set of more structurally related genes changed their expression only after a delay of 2 d (7). Lung structure, analyzed by conventional 2D histology and also by 3D reconstruction using synchrotron x-ray tomographic microscopy revealed, 48 h after end of MV, a reduced complexity of lung architecture compared to the nonventilated rat lungs, similar to the typical findings in BPD. To extend these observations about late gene expression modifications, we performed with a similar model a full gene expression profile of lung tissue 48 h after the end of MV with either room air or 60% oxygen. Essentially, we measured changes in the expression of genes related to the MMPs and complement system which played a role in many of the six identified mostly affected pathways.