Francesco G. Salerno

IL-2, TNF-α, and Leptin: Local Versus Systemic Concentrations in NSCLC Patients

One recent line of cancer research shows increasing interest for biological factor such as IL-2, TNF-α, and leptin, which have been found to participate in the development and progression of non-small cell lung cancer (NSCLC). The aim of this study was to measure IL-2, TNF-α, and leptin concentrations in the airways and in the systemic circle of patients with NSCLC, investigating the role of these factors in the lung tumors. We enrolled 32 patients (17 men, 71 ± 7 years) with a histological diagnosis of NSCLC and 20 healthy ex-smoker controls, negative for computed tomography of the chest (14 men, 69 ± 8 years). IL-2, TNF-α, and leptin levels were measured in the serum, the urine, the bronchoalveolar lavage, the induced sputum, and exhaled breath condensate (EBC) of patients enrolled by means of a specific enzyme immunoassay kit. Higher concentrations of IL-2, TNF-α and leptin were found in NSCLC patients than in controls (p < 0.0001). A statistically significant increase of IL-2, TNF-α, and leptin concentrations was observed in patients from stage I to stage III of NSCLC. These findings suggest that IL-2, TNF-α, and the leptin play an important role in the cancerogenesis of NSCLC. Their measure in the EBC could be proposed as noninvasive markers for an early detection of NSCLC and in the follow-up of this tumor.

Stretch-induced changes in constricted lung parenchymal strips: role of extracellular matrix

Large amplitude oscillations of contracted airway smooth muscle cause relative relaxation of the preparation. However, little is known about the effect of mechanical stretch on distal lung behaviour. Rat parenchymal strips were suspended in an organ bath and attached at one end to a force transducer and at the other end to a servo-controlled lever arm that effected length changes. Mechanical impedance of the strip was measured by applying a complex signal consisting of pseudorandom length oscillations of varying frequencies (0.5–19.75 Hz). A constant phase model was fit to changes in length and tension to calculate tissue damping (G) and elastance (H). Hysteresivity was calculated as G/H. Impedance was measured before and after sinusoidal length oscillation at different amplitudes (1, 3, 10 and 25% of resting length) at a frequency of 1 Hz under baseline conditions and after acetylcholine-induced constriction. Oscillations of 10 and 25% amplitudes significantly decreased the G and H of the lung strip. The effect of length oscillations was no different in control versus constricted strips. These data suggest that in the distal lung, large stretches affect the structural components of the extracellular matrix rather than the contractile elements.

Characterization of the anatomical structures involved in the contractile response of the rat lung periphery

1 When lung parenchymal strips are challenged with different smooth muscle agonists, the tensile and viscoelastic properties change. It is not clear, however, which of the different anatomical elements present in the parenchymal strip, i.e., small vessel, small airway or alveolar wall, contribute to the response. 2 Parenchymal lung strips from Sprague Dawley rats were suspended in an organ bath filled with Krebs solution (37°C, pH = 7.4) bubbled with 95%O2/5%CO2. Resting tension (T) was set at 1.1 g and sinusoidal oscillations of 2.5% resting length (Lo) at a frequency of 1 Hz were applied. Following 1 h of stress adaptation, measurements of length (L) and T were recorded under baseline conditions and after challenge with a variety of pharmacological agents, i.e., acetylcholine (ACh), noradrenaline (NA) and angiotensin II (AII). Elastance (E) and resistance (R) were calculated by fitting changes in T, L and ΔL/Δt to the equation of motion. Hysteresivity (η, the ratio of the energy dissipated to that conserved) was obtained from the equation η = (R/E)2πf. 3 In order to determine whether small airways or small vessels accounted for the responses to the different pharmacologic agents, further studies were carried out in lung explants. Excised lungs from Sprague Dawley rats were inflated with agarose. Transverse slices of lung (0.5–1.0 mm thick) were cultured overnight. By use of an inverted microscope and video camera, airway and vascular lumen area were measured with an image analysis system. 4 NA, ACh and AII constricted the parenchymal strips. Airways constricted after all agonists, vessels constricted only after AII. Atropine (Atr) pre‐incubation decreased the explanted airway and vessel response to AII, but no difference was found in the parenchymal strip response. 5 Preincubation with the arginine analogue Nω‐nitro‐L‐arginine (L‐NOARG) did not modify the response to ACh but mildly increased the oscillatory response to NA after co‐preincubation with propranolol (Prop). 6 These results suggest that during ACh and NA challenge, small vessels do not contribute substantially to the parenchymal strip response. The discrepancy between results in airways, vessels and strips when Atr was administered prior to AII implicates a direct contractile response in the parenchymal strip.

Italian Registry of Patients with Alpha-1 Antitrypsin Deficiency: General Data and Quality of Life Evaluation

Abstract Alpha1-antitrypsin Deficiency (AATD) is a rare hereditary disorder with an estimated prevalence of about 1/5000 individuals in Italy. Deficient patients are at a higher risk of developing lung emphysema and chronic liver disease. The low estimated prevalence of AATD prompted the establishment of a registry with the aim of learning more about the natural history and the quality of care of these patients. The Italian registry for AATD was established in 1996. In this study, genetic and clinical findings of Italian AATD patients are presented. Moreover, we also evaluated the changes in health-related quality of life (HRQoL) in patients with COPD and AAT deficiency over a three-year period, in relation to augmentation therapy. In a period spanning 18 years (1996–2014) a total of 422 adult subjects with severe AATD were enrolled, namely 258 PI*ZZ, 74 PI*SZ, 4 PI*SS and 86 patients with at least one rare deficient allele. The 21.3% frequency for AATD patients with at least one deficient rare variant is the highest so far recorded in national registries of AATD. The registry data allow a detailed characterization of the natural course of the disease and the level of patient care, as well as confirm the usefulness of early AATD detection.

Effect of CPAP-therapy on bronchial and nasal inflammation in patients affected by obstructive sleep apnea syndrome*

BACKGROUND Obstructive sleep apnea syndrome (OSAS) has been shown to be associated to upper and lower airways inflammation. Continuous positive airway pressure (CPAP) is the elective treatment of OSAS. The aim of the present study was to assess the effect of CPAP-therapy on airway and nasal inflammation. METHODS In 13 non-smoking subjects affected by untreated OSAS and in 11 non-smoking normal volunteers, airway inflammation was detected by analyses of the induced sputum. In the OSAS group measurements were repeated after 1, 10 and 60 days of the appropriate CPAP treatment. In addition, in 12 subjects of the OSAS group, nasal inflammation was detected by the analysis of induced nasal secretions at baseline, and after 1, 10 and 60 days of CPAP treatment. RESULTS OSAS patients, compared to normal controls, showed at baseline a higher percentage of neutrophils and a lower percentage of macrophages in the induced sputum. One, 10 and 60 days of appropriate CPAP-therapy did not change the cellular profile of the induced sputum. In addition, in the OSAS patients, the high neutrophilic nasal inflammation present under baseline conditions was not significantly modified by CPAP-therapy. Finally, no patients developed airway hyper-responsiveness after CPAP therapy. CONCLUSIONS In OSAS subjects, the appropriate CPAP-therapy, while correcting the oxygen desaturation, does not modify the bronchial and nasal inflammatory profile.

Effect of the route and mode of agonist delivery on functional behaviour of the airways

There is evidence that the mode of smooth muscle agonist delivery affects the changes induced in lung mechanical properties. The object of this investigation was to study modifications in airway behaviour associated with different modes of agonist delivery. Tracheal (Ptr) and alveolar pressure (PA) and flow (V) were measured in open-chested, mechanically ventilated (f = 1 Hz, VT = 10 ml/kg, PEEP = 4 cm H2O) rats under baseline conditions and during administration of repeated intravenous (i.v.) bolus, i.v. continuous infusion and aerosols of methacholine (MCh). We calculated lung elastance (EL) and lung resistance (RL) by fitting the equation of motion to changes in Ptr and V. We assessed the patency of the airway pathways and local dynamic hyperinflation by comparing Ptr vs PA. Comparison of the three different modes of MCh delivery showed a difference in the functional behaviour of the airways. In the aerosol group a larger incidence of highly constricted airways was observed. Conversely, the i.v. groups showed a larger incidence of regional dynamic hyperinflation. In the bolus group a different time course in the development of dynamic hyperinflation was observed for different pathways within the same animal. For consecutive challenges a given pathway tended to behave in the same manner, suggesting the response was characteristic for that pathway. In this study we have shown that, even though different airway pathways show different intrinsic reactivity, the mode of agonist delivery plays a role in determining functional airway behaviour.

Airway cell patterns in patients suffering from COPD and OSAS (Overlap Syndrome).

BACKGROUND Obstructive sleep apnea syndrome (OSAS) and chronic obstructive pulmonary disease (COPD) are two diseases that often coexist within an individual. This coexistence is known as Overlap Syndrome (OS). Both diseases are characterized by local and systemic inflammations, but no studies to date have investigated local airway inflammation in patients suffering from Overlap Syndrome. METHODS We performed a Berlin Questionnaire to evaluate the presence of the principal OSAS symptoms, a pulmonary function test, and then a nocturnal oximetry and polysomnography in 72 patients that were divided into five groups: OS (n = 18), COPD (n = 15), OSAS (n = 16), 12 obese without OSAS or COPD, and one control group of 11 normal subjects. All patients underwent sputum induction and the analysis of cell patterns were evaluated in all groups. The relationship with the degree of obesity, airway obstruction and OSAS severity was also evaluated. RESULTS The percentage of neutrophils in induced sputum was higher in OS (74.33% ± 14.8), COPD (63.33% ± 13.22) and OSAS (60.69% ± 17.6) subjects compared with control groups of obese (43.5% ± 17.49) and normal weight (32.04% ± 12.26). No difference was found among Overlap, COPD, and OSAS patients (p = 0.56). A negative correlation was found between PaO(2) and percentage of airway neutrophils (r = -0.29, p < 0.05); similarly, no correlations arose between BMI, FEV(1) or ODI. CONCLUSION Patients suffering from Overlap Syndrome present a high percentage of neutrophils in induced sputum like patients affected by COPD or OSAS alone. Our result suggests that airway inflammations is always involved in all of these diseases, even though probably sustained by different mechanisms.

Management of acute respiratory failure in interstitial lung diseases: overview and clinical insights

BackgroundInterstitial lung diseases (ILDs) are a heterogeneous group of diseases characterized by widespread fibrotic and inflammatory abnormalities of the lung. Respiratory failure is a common complication in advanced stages or following acute worsening of the underlying disease. Aim of this review is to evaluate the current evidence in determining the best management of acute respiratory failure (ARF) in ILDs.MethodsA literature search was performed in the Medline/PubMed and EMBASE databases to identify studies that investigated the management of ARF in ILDs (the last search was conducted on November 2017).ResultsIn managing ARF, it is important to establish an adequate diagnostic and therapeutic management depending on whether the patient has an underlying known chronic ILD or ARF is presenting in an unknown or de novo ILD. In the first case both primary causes, such as acute exacerbations of the disease, and secondary causes, including concomitant pulmonary infections, fluid overload and pulmonary embolism need to be investigated. In the second case, a diagnostic work-up that includes investigations in regards to ILD etiology, such as autoimmune screening and bronchoalveolar lavage, should be performed, and possible concomitant causes of ARF have to be ruled out.Oxygen supplementation and ventilatory support need to be titrated according to the severity of ARF and patients’ therapeutic options. High-Flow Nasal oxygen might potentially be an alternative to conventional oxygen therapy in patients requiring both high flows and high oxygen concentrations to correct hypoxemia and control dyspnea, however the evidence is still scarce. Neither Non-Invasive Ventilation (NIV) nor Invasive Mechanical Ventilation (IMV) seem to change the poor outcomes associated to advanced stages of ILDs. However, in selected patients, such as those with less severe ARF, a NIV trial might help in the early recognition of NIV-responder patients, who may present a better short-term prognosis. More invasive techniques, including IMV and Extracorporeal Membrane Oxygenation, should be limited to patients listed for lung transplant or with reversible causes of ARF.ConclusionsDespite the overall poor prognosis of ARF in ILDs, a personalized approach may positively influence patients’ management, possibly leading to improved outcomes. However, further studies are warranted.

Obstructive lung function decline and IPF: The dark face of the moon.

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease that causes inflammation, scarring, thickening, and stiffening of the lung tissues. The disease is progressive, generally fatal, and causes an irreversible loss of the tissue’s ability to transport oxygen. However, the prognosis is variable and in some cases a great difficult task for pulmonologists. It is therefore important to determine appropriate determinant factors that may help in predicting the survival and rationale therapeutic interventions. In this line, we have read with great interest the study by Nishiyama et al. that confirms this poor outcome in IPF. In this original observation, Nishiyama et al. hypothesized that the forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) ratio has an impact on prognosis. The results reported have practical implications, however, there are some key aspects on how chronic airway obstruction could impact on IPF. From a methodology point of view, in order to answer to this question, authors examined retrospectively more than 100 patients and a correlation was found between FEV1/FVC and survival. Intriguingly, lower FEV1/FVC was associated with longer survival, making the patients with a lower FEV1/FVC ratio to have a more favorable prognosis as compared to the patients with higher FEV1/FVC ratio. In our opinion, it is difficult to find a clear explanation of this observation. The authors speculate that, somehow, smoke may be ‘‘good’’ for the IPF patients (i.e. smoke may inhibit fibroblast proliferation, or decrease the numbers of exacerbations, or determine a slower decrease in lung function). However, it is known that lung fibrosis increases lung elastic recoil. Lung elastic recoil affects the driving pressure that determines the velocity of lung emptying, and we may argue that as the disease progresses, because of the higher elastic recoil of the stiff lungs, the FEV1/FVC ratio may become higher or higher than normal. Ultimately, a lower FEV1/FVC ratio may be, somehow, a marker of a less advanced disease. We consider that to investigate these mechanisms, it would be interesting to measure in these patients transpulmonary pressure and therefore calculate real lung compliance. This approach could give us a more objective and appropriate interpretation of the FEV1/FVC ratio. There is a lack of information regarding lung function decline in respiratory symptomatic patients. The real impact of FEV1, 4 and other well-known key prognosis factors, as pulmonary artery hypertension should be investigated. We consider that it is necessary to know whether this variation in FEV1/FVC is related to the severity of IPF or to other variables. In conclusion, although Nishiyama et al. have made the interesting observation that FEV1/FVC ratio has an impact on survival in IPF patients, further studies are needed to understand the real physiological mechanisms involved.