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Chronic interstitial lung abnormalities have been described in sickle cell disease (SCD) and attributed to repetitive episode of acute chest syndrome. We report a series of 22 cases of diffuse cystic lung disease in SCD with a case–control study to hunt for mechanism. On pathological analysis of a surgical lung biopsy of the index case, the bronchioles had the appearance of constrictive bronchiolitis. Pulmonary function test results revealed lower forced expiratory flow from 25% to 75% of vital capacity in cases versus controls. These findings suggest a bronchiolar mechanism that was not associated with more acute chest syndrome.

Supplemental Digital Content is available in the text

Supplemental Digital Content is available in the text.

Recent hemodynamic studies performed in large cohorts of adult patients with sickle cell disease have established the prevalence of pulmonary hypertension in this diseaseabout 6 to 10%. Over half of these correspond to postcapillary pulmonary hypertension.

Pulmonary artery remodeling triggered by alveolar hypoxia is considered the main mechanism of pulmonary hypertension (PH) in COPD patients. We hypothesized that the risk for PH in COPD is increased by an elevation in the proinflammatory cytokines interleukin (IL)-6, monocyte chemoattractant protein-1 (MCP-1), and IL-1β, as well as by specific genetic polymorphisms of these cytokines.

Sampling techniques for microbiological diagnosis of ventilator-associated pneumonia (VAP) remain debated, and it is unclear to what extent invasive diagnostic techniques impact the management of patients

High concentrations of oxygen can induce pulmonary toxicity and cause injury to alveolar epithelial and endothelial cells. The present study was performed to determine whether the potent epithelial and endothelial fibroblast growth factor 1 (FGF-1) protected against hyperoxia-induced lung injury. Recombinant adenovirus carrying the gene encoding human secreted FGF-1 (Ad. FGF1) increased the proliferation of lung epithelial cells in vitro. Ad.FGF1 or control vector with an empty expression cassette (Ad.V152) was administered intratracheally to Wistar rats. With Ad.FGF1 (109, 5 × 109, 1010, or 5 × 1010 viral particles [VP]), FGF-1 protein was found in bronchoalveolar lavage fluid 4 days postinfection at levels proportional to the viral dose and was detected in plasma after doses of 1010 VP or more were administered. Histological examination of the lungs showed intense proliferation and apoptosis of alveolar and bronchial epithelial cells, with few inflammatory cells. The alveolar architecture returned to normal within 17 days. Rats pretreated with Ad.FGF1 (109 or 5 × 109 VP) 2 days before exposure to hyperoxia (95% O2) survived, whereas rats pretreated with Ad.V152 died within 3 days. In conclusion, adenovirus-mediated FGF-1 overexpression in the lungs causes epithelial cell proliferation and has beneficial effects in hyperoxic lung injury.

ABSTRACTBordetella pertussis, the agent of whooping cough, can invade and survive in several types of eukaryotic cell, including CHO, HeLa 229, and HEp-2 cells and macrophages. In this study, we analyzed bacterial invasiveness in nonrespiratory human HeLa epithelial cells and human HTE and HAE0 tracheal epithelial cells. Invasion assays and transmission electron microscopy analysis showed that B. pertussisstrains invaded and survived, without multiplying, in HTE or HAE0 cells. This phenomenon was bvgregulated, but invasive properties differed between B. pertussisstrains and isolates and the B. pertussisreference strain. Studies with B. pertussismutant strains demonstrated that filamentous hemagglutinin, the major adhesin, was involved in the invasion of human tracheal epithelial cells by bacteria but not in that of HeLa cells. Fimbriae and pertussis toxin were not found to be involved. However, we found that the production of adenylate cyclase-hemolysin prevents the invasion of HeLa and HTE cells byB. pertussisbecause an adenylate cyclase-hemolysin-deficient mutant was found to be more invasive than the parental strain. The effect of adenylate cyclase-hemolysin was mediated by an increase in the cyclic AMP concentration in the cells. Pertactin (PRN), an adhesin, significantly inhibited the invasion of HTE cells by bacteria, probably via its interaction with adenylate cyclase-hemolysin. Isolates producing different PRNs were taken up similarly, indicating that the differences in the sequences of the PRNs produced by these isolates do not affect invasion. We concluded that filamentous hemagglutinin production favored invasion of human tracheal cells but that adenylate cyclase-hemolysin and PRN production significantly inhibited this process.

The alveolar surface of the lung is a major target for oxidant injury, and its repair following injury is dependent on the ability of its stem cells, the type 2 cells, to initiate proliferation. From previous studies it is likely that events located before the entry into the S phase of the cell cycle and involving several components of the insulin-like growth factor system as well as of transforming growth factor-β (TGF-β) play a key role in growth regulation of oxidant-exposed type 2 epithelial cells. To gain further insights into these mechanisms, we explored the effects of O2exposure on G1cyclins and their cyclin-dependent kinases (CDKs). We documented an increased expression of these genes in O2-treated type 2 cells. However, despite this induction, a dramatic decrease in cyclin E-CDK2 activity, but not in cyclin D-CDK4 activity, was found. The concomitant induction of CDK inhibitory proteins (CKIs), mainly p21CIP1, suggests that accumulation of inactive cyclin E-CDK2 activity is due to CKI binding. We also provided evidence that the mechanisms regulating this process involved TGF-β as anti-TGF-β antibody treatment was able to reduce the oxidant-induced inhibition of cyclin E-CDK2 activity. Taken together, these results suggest that oxidants may block entry into S phase by acting on a subset of late G1events whose alterations are sufficient to impair the activation of cyclin E-CDK2 complexes.

Bartolucci: Addmedica: Research Funding; GBT: Membership on an entity's Board of Directors or advisory committees; Fondation Fabre: Research Funding; Novartis US: Membership on an entity's Board of Directors or advisory committees.

Introduction

No relevant conflicts of interest to declare.

Supplemental Digital Content is available in the text

Production of abnormal hemoglobin (HbS) in sickle-cell disease (SCD) results in its polymerization in deoxygenated conditions and in sickled-RBC formation. Dense RBCs (DRBCs), defined as density >1.11 and characterized by increased rigidity, viscosity and HbS concentration (main polymerization factor), are absent in normal AA subjects, but present at percentages that vary from 1 SCD patient to another but remain stable throughout adulthood for each patient. Polymerized, but not nonpolymerized, HbS has reduced affinity for oxygen, demonstrated by the rightward shift of the oxygen-dissociation curve, leading to disturbances in oxygen transport. We recently described a correlation between %DRBCs and some clinical SCD manifestations. Notably, some SCD patients have unexplained, very low oxygen saturation (SpO2), without heart or lung dysfunctions. %DRBC variability within SCD patients could be the main pathophysiological explanation of those manifestations. This study was undertaken to determine whether a link exists between the %DRBCs and Hb affinity for oxygen, and to look for a potential clinical implication for SCD patients.

Pulmonary hypertension (PH) has emerged as life threatening complication in patients with sickle cell disease. It is usually diagnosed at echocardiography by estimating systolic Pulmonary Artery Pressure (PAP) through the measurement of a velocity of tricuspid regurgitation (TRV) > 2.5 m/s. Pulmonary Hypertension diagnosed as so could affect up to 30% of patients with sickle cell disease (SCD). However, according to most guidelines, PH is rather defined by measurement of mean PAP ≥ 25 mmHg at right heart catheterism. Whether measurement of TRV ≥ 2.5 m/s at echocardiography accurately identifies patients with PH in patients with SCD, has never been evaluated.We conducted a prospective multicentre study in 403 consecutive adult out-patients in stable clinical condition, recruited after informed consent, during 2 years (from Feb.2007 to March 2009) from 2 SCD referral centers in France (1 in Paris and 1 in Martinique). Follow -up was planned for 3 years. All patients had Doppler echocardiography, pulmonary function tests and 6 min walk test. RHC was systematically performed in case of TRV3 2.5m/sec.Of the 385/403 patients (SS in 379, 6 Sb0thalassemia) with all data availabel, sex ratio 1.5 , mean age 34±10 yrs, 96 had TRV 3 2.5m/s (25 %) and underwent RHC. There was no PH in 72/96 with mPAp=19 ±3mmHg (false positive of echocardiography=75%). In 24 patients, m PAP was elevated (30 ± 0.4m/s). Mechanism of PH was: post-capillary PH in 13 patients (elevated pulmonary capillary wedge pressure) - hyperkinetic state in 5 patients (high cardiac output, normal pulmonary vascular resistance) - pre-capillary pulmonary arterial hypertension (PAH) in 6 patients (normal capillary wedge pressure, increased vascular resistance). Patients with a confirmed PH at RHC were significantly older (45 vs 33 yrs), had higher LDH, NT-Pro BNP, and a lower 6 min walk distance. There was no influence of long term treatment (hydroxyurea, chronic transfusion) on PH.During follow-up (mean=11 months), 3 patients died, all in the group of patients with TRV32.5 m/sec and confirmed PH at RHC (mPAP 3 25 mmHg). The 24 patients having confirmed PH with RHC display similar biological and hemodynamic profile to the 18/42 with TRV3 2.5m/sec among the 195 patients (132 SS,35SC,23S-Thalassemia b0or b+) of the Gladwin study(1), consenting to have RHC. The use of a higher cut-off value of TRV, 2.8 m/sec, decreases the false positive rate from 75% to 50%. However, 29% of patients with pulmonary hypertension (7/24) would have been undiagnosed.PH confirmed by gold-standard technique (RHC) is relatively rare among SCD patients, with a prevalence of 24/385 (6%). PAH was present in only 6 patients (1.6%). In this population, a TRV 2.5m/s on Doppler echocardiography is inadequate to diagnose PH. The loose relationship found between TRV and pulmonary hypertension in patients with sickle cell disease does not support its use as a routine screening tool, whatever the cut-off used. Although PH on RHC was generally modest, PH seems to be an important prognostic factor. The large difference on mortality compared to previous studies will be discussed.No relevant conflicts of interest to declare.

Abstract 572