Lung Stiffness Research Articles

Older age at Fontan completion is associated with reduced lung volumes and increased lung reactance

BackgroundFontan patients have abnormal lung function, in particular restrictive lung disease and low diffusing capacity of carbon monoxide (DLCO). We sought to further characterise these abnormalities with detailed pulmonary function testing and examine associations with clinical parameters. Methods132 Fontan patients across Australia and New Zealand underwent spirometry, with 126 subjects included in final analyses. Measurement of diffusion capacity (DLCO) including its components (alveolar volume (VA) and rate of uptake of CO (KCO)) and oscillometry (reactance (X5) and resistance (R5)) were assessed in a subset of Fontan patients (n = 44) and healthy controls (n = 12). Double diffusion (to assess diffusing capacity of nitric oxide (DLNO), capillary blood volume (Vc), alveolar capillary membrane function (DmCO)) was performed in Fontan patients (n = 18) and healthy controls (n = 12). ResultsFEV1 and FVC z-scores were low in Fontan subjects (mean − 1.67 ± 1.24 and − 1.61 ± 1.29, respectively) and correlated with exercise capacity. Compared to controls, z-scores for X5, DLCO, KCO, VA and DLNO were significantly lower in Fontan patients. R5, Vc and DmCO z-scores were preserved. X5 was associated with VA (r = 0.41,p = 0.009) and DmCO (r = 0.61,p = 0.008). Older age at Fontan completion was associated with lower z-scores for FEV1 (r = −0.46,p = 0.002), FVC (r = −0.47,p = 0.002), X5 (r = −0.32,p = 0.033) and VA (r = −0.36,p = 0.022). ConclusionFontan patients have a reduced DLCO which is largely driven by low VA. Lung stiffness (X5) is increased which is associated with VA and DmCO. These parameters negatively correlate with older age of Fontan completion suggesting that earlier Fontan completion may have a beneficial effect on lung function.

Forced Vital Capacity and Low Frequency Reactance Area Measurements Are Associated with Asthma Control and Exacerbations

IntroductionForced vital capacity (FVC) is often preserved in severe asthma unless there is evidence of either airway remodelling or air trapping. Area under the reactance curve (AX) can be used to assess small airways dysfunction related lung stiffness and is related to disease control in severe asthma.MethodsWe explore if there may be a potential synergistic interaction between FVC and AX in terms of impaired asthma control as ACQ and exacerbations requiring oral corticosteroids (OCS). We pragmatically defined < 100% and ≥ 1.0 kPa/L/s as impaired FVC or AX, respectively. ResultsPatients with combined impairment of FVC and AX had significantly worse asthma control as higher ACQ, more severe exacerbations requiring OCS and worse spirometry (FEV1 and FEF25–75) than those with impaired FVC but preserved AX.ConclusionThis in turn supports using both spirometry and oscillometry to characterise airway physiology more comprehensively in patients with more severe asthma.

Preclinical and Toxicology Studies of BRD5529, a Selective Inhibitor of CARD9.

BackgroundThe caspase recruitment domain-containing protein 9 (CARD9) inhibitor BRD5529 has been shown to be an effective in vitro inhibitor of Pneumocystis β-glucan-induced proinflammatory signaling, suggesting its viability as a candidate for preliminary anti-Pneumocystis drug testing in the rodent Pneumocystis pneumonia (PCP) model.MethodsMice were injected intraperitoneally (IP) daily with either vehicle or BRD5529 at 0.1 or 1.0 mg/kg for 2 weeks. Mouse weights were taken daily. At day 14, mice were euthanized, weighed, and analyzed by flexiVent™ for lung stiffness. Lungs, liver, and kidney were then harvested for hematoxylin and eosin (H&E) staining and pathology scoring. Lung samples were further analyzed for proinflammatory cytokines via enzyme-linked immunosorbent assay (ELISA) and extracellular matrix generation via quantitative polymerase chain reaction (qPCR). Blood collection postmortem was performed for blood chemistry analysis. Furthermore, administration of BRD5529 prior to the intratracheal inoculation of fungal β-glucans, which are known proinflammatory mediators via the Dectin-1-CARD9 pathway, resulted in significant reductions in lung tissue interleukin-6 and tumor necrosis factor-α, suggesting the exciting possibility of the use of this CARD9 inhibitor as an additional therapeutic tool in fungal infections.ResultsBRD5529 at both IP doses resulted in no significant changes in daily or final weight gain, and analysis of lung stiffness by flexiVent™ showed no significant differences between the groups. Furthermore, ELISA results of proinflammatory cytokines showed no major differences in the respective groups. qPCR analysis of extracellular matrix transcripts were statistically similar. Examination and pathology scoring of H&E slides from lung, liver, and kidney in all groups, as well as subsequent pathology scoring, showed no significant change. Blood chemistry analysis revealed similar, non-significant patterns.ConclusionsIn our initial general safety and toxicology assessments, BRD5529 displayed no inherent safety concerns in the analyzed parameters. These data support broader in vivo testing of the inhibitor as a timed adjunct therapy to the deleterious proinflammatory host immune response often associated with anti-Pneumocystis therapy.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40268-022-00389-0.

Combining low-frequency oscillometry and spirometry measurements in relation to asthma control and exacerbations in moderate-to-severe asthma

Combining low-frequency oscillometry and spirometry measurements in relation to asthma control and exacerbations in moderate-to-severe asthma

Impact of the Amyotrophic Lateral Sclerosis Disease on the Biomechanical Properties and Oxidative Stress Metabolism of the Lung Tissue Correlated With the Human Mutant SOD1G93A Protein Accumulation.

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease, and ALS incidence is increasing worldwide. Patients with ALS have respiratory failure at the disease’s end stages, leading to death; thus, the lung is one of the most affected organs during disease progression. Tissue stiffness increases in various lung diseases because of impaired extracellular matrix (ECM) homeostasis leading to tissue damage and dysfunction at the end. According to the literature, oxidative stress is the major contributor to ECM dysregulation, and mutant protein accumulation in ALS have been reported as causative to tissue damage and oxidative stress. In this study, we used SOD1G93A and SOD1WT rats and measured lung stiffness of rats by using a custom-built stretcher, where H&E staining is used to evaluate histopathological changes in the lung tissue. Oxidative stress status of lung tissues was assessed by measuring glucose 6-phosphate dehydrogenase (G6PD), 6-phosphogluconate dehydrogenase (6-PGD), glutathione reductase (GR), glutathione s-transferase (GST), catalase (CAT), and superoxide dismutase 1 (SOD1) levels. Western blot experiments were performed to evaluate the accumulation of the SOD1G93A mutated protein. As a result, increased lung stiffness, decreased antioxidant status, elevated levels of oxidative stress, impaired mineral and trace element homeostasis, and mutated SOD1G93A protein accumulation have been found in the mutated rats even at the earlier stages, which can be possible causative of increased lung stiffness and tissue damage in ALS. Since lung damage has altered at the very early stages, possible therapeutic approaches can be used to treat ALS or improve the life quality of patients with ALS.

Nitrofen rat model of congenital diaphragmatic hernia demonstrates increased lung stiffness using shear wave elastography

Patients with congenital diaphragmatic hernia (CDH) have intrinsic lower lung compliance. Shear wave elastography (SWE) is an emerging noninvasive ultrasound technology to evaluate fetal lung stiffness with the potential to correlate with histopathologic analyses and postnatal pulmonary function. We aimed to evaluate lung elastography measurements in a nitrofen rat model of CDH.

Dynamic lung compliance imaging from 4DCT-derived volume change estimation

Background. Lung compliance (LC) is the ability of the lung to expand with changes in pressure and is one of the earliest physiological measurements to be altered in patients with parenchymal lung disease. Therefore, compliance monitoring could potentially identify patients at risk for disease progression. However, in clinical practice, compliance measurements are prohibitively invasive for use as a routine monitoring tool. Purpose. We propose a novel method for computing dynamic lung compliance imaging (LCI) from non-contrast computed tomography (CT) scans. LCI applies image processing methods to free-breathing 4DCT images, acquired under two different continuous positive airway pressures (CPAP) applied using a full-face mask, in order to compute the lung volume change induced by the pressure change. LCI provides a quantitative volumetric map of lung stiffness. Methods. We compared mean LCI values computed for 10 patients with idiopathic pulmonary fibrosis (IPF) and 7 non-IPF patients who were screened for lung nodules. 4DCTs were acquired for each patient at 5 cm and 10 cm H20 CPAP, as the patients were free breathing at functional residual capacity. LCI was computed from the two 4DCTs. Mean LCI intensities, which represent relative voxel volume change induced by the change in CPAP pressure, were computed. Results. The mean LCI values for patients with IPF ranged between [0.0309, 0.1165], whereas the values ranged between [0.0704, 0.2185] for the lung nodule cohort. Two-sided Wilcoxon rank sum test indicated that the difference in medians is statistically significant (p value = 0.009) and that LCI -measured compliance is overall lower in the IPF patient cohort. Conclusion. There is considerable difference in LC scores between patients with IPF compared to controls. Future longitudinal studies should look for LC alterations in areas of lung prior to radiographic detection of fibrosis to further characterize LCI’s potential utility as an image marker for disease progression.

Free-breathing MR elastography of the lungs: An in vivo study.

Lung stiffness alters with many diseases; therefore, several MR elastography (MRE) studies were performed earlier to investigate the stiffness of the right lung during breathhold at residual volume and total lung capacity. The aims of this study were 1) to estimate shear stiffness of the lungs using MRE under free breathing and demonstrate the measurements' repeatability and reproducibility, and 2) to compare lung stiffness under free breathing to breathhold and as a function of age and gender. Twenty-five healthy volunteers were scanned on a 1.5 Tesla MRI scanner. Spin-echo dual-density spiral and a spin-echo EPI MRE sequences were used to measure shear stiffness of the lungs during free breathing and breathhold at midpoint of tidal volume, respectively. Concordance correlation coefficient and Bland-Altman analyses were performed to determine the repeatability and reproducibility of the spin-echo dual-density spiral-derived shear stiffness. Repeated measures analyses of variances were used to investigate differences in shear stiffness between spin-echo dual-density spiral and spin-echo EPI, right and left lungs, males and females, and different age groups. Free-breathing MRE sequence was highly repeatable and reproducible (concordance correlation coefficient > 0.86 for both lungs). Lung stiffness was significantly lower in breathhold than in free breathing (P < .001), which can be attributed to potential stress relaxation of lung parenchyma or breathhold inconsistencies. However, there was no significant difference between different age groups (P = .08). The left lung showed slightly higher stiffness values than the right lung (P = .14). There is no significant difference in lung stiffness between genders. This study demonstrated the feasibility of free-breathing lung MRE with excellent repeatability and reproducibility. Stiffness changes with age and during the respiratory cycle. However, gender does not influence lungs stiffness.

Associations between respiratory and vascular function in early childhood.

The link between respiratory and vascular health is well documented in adult populations. Impaired lung function is consistently associated with thicker arteries and higher incidence of cardiovascular disease. However, there are limited data on this relationship in young children and the studies that exist have focussed on populations at high risk of cardiorespiratory morbidity. We determined if an association exists between respiratory and cardiovascular function in young children and, if so, whether it is confounded by known cardiorespiratory risk factors. Respiratory and vascular data from a prospective cohort study established to evaluate the health implications 3 years after coal mine fire smoke exposure in children aged 3-5 years were used. Respiratory function was measured using the forced oscillation technique and included resistance at 5Hz (R5 ), reactance at 5Hz (X5 ) and area under the reactance curve (AX). Vascular health was measured by carotid intima-media thickness (ultrasound) and pulse wave velocity (arterial tonometry). Regression analyses were used to examine the relationship between the respiratory Z-scores and cardiovascular measures. Subsequent analyses were adjusted for potential confounding by maternal smoking during pregnancy, maternal education and exposure to fine particulate matter <2.5μm in aerodynamic diameter (PM2.5 ). Peripheral lung function (X5 and AX), but not respiratory system resistance (R5 ), was associated with vascular function. Adjustment for maternal smoking, maternal education and early life exposure to PM2.5 had minimal effect on these associations. These observations suggest that peripheral lung stiffness is associated with vascular stiffness and that this relationship is established early in life.

MR elastography inversion by compressive recovery

Direct inversion (DI) derives tissue shear modulus by inverting the Helmholtz equation. However, conventional DI is sensitive to data quality due to the ill-posed nature of Helmholtz inversion and thus providing reliable stiffness estimation can be challenging. This becomes more problematic in the case of estimating shear stiffness of the lung in which the low tissue density and short T2* result in considerably low signal-to-noise ratio during lung MRE. In the present study, we propose to perform MRE inversion by compressive recovery (MICRo). Such a technique aims to improve the numerical stability and the robustness to data noise of Helmholtz inversion by using prior knowledge on data noise and transform sparsity of the stiffness map. The developed inversion strategy was first validated in simulated phantoms with known stiffness. Next, MICRo was compared to the standard clinical multi-modal DI (MMDI) method for in vivo liver MRE in healthy subjects and patients with different stages of liver fibrosis. After establishing the accuracy of MICRo, we demonstrated the robustness of the proposed technique against data noise in lung MRE with healthy subjects. In simulated phantoms with single-directional or multi-directional waves, MICRo outperformed DI with Romano filter or Savitsky and Golay filter, especially when the stiffness and/or noise level was high. In hepatic MRE application, agreement was observed between MICRo and MMDI. Measuring in vivo lung stiffness, MICRo demonstrated its advantages over filtered DI by yielding stable stiffness estimation at both residual volume and total lung capacity. These preliminary results demonstrate the potential value of the proposed technique and also warrant further investigation in a larger clinical population.

Lung Ultrasound Surface Wave Elastography for Assessing Patients With Pulmonary Edema.

B-Mode ultrasound insonation of lungs that are dense with extravascular lung water (EVLW) produces characteristic reverberation artifacts termed B-lines. The number of B-lines present demonstrates reasonable correlation to the amount of EVLW. However, analysis of B-line artifacts generated by this modality is semi-quantitative relying on visual interpretation, and as a result, can be subject to inter-observer variability. The purpose of this study was to translate the use of a novel, quantitative lung ultrasound surface wave elastography technique (LUSWE) into the bedside assessment of pulmonary edema in patients admitted with acute congestive heart failure. B-mode lung ultrasound and LUSWE assessment of the lungs were performed using anterior and lateral intercostal spaces in the supine patient. 14 patients were evaluated at admission with reassessment performed 1-2 days after initiation of diuretic therapy. Each exam recorded the total lung B-lines, lung surface wave speeds (at 100, 150, and 200 Hz) and net fluid balance. The patient cohort experienced effective diuresis (average net fluid balance of negative 2.1 liters) with corresponding decrease in pulmonary edema visualized by B-mode ultrasound (average decrease of 13 B-Lines). In addition, LUSWE demonstrated a statistically significant reduction in the magnitude of wave speed from admission to follow-up. The reduction in lung surface wave speed suggests a decrease in lung stiffness (decreased elasticity) mediated by successful reduction of pulmonary edema. In summary, LUSWE is a noninvasive technique for quantifying elastic properties of superficial lung tissue that may prove useful as a diagnostic test, performed at the bedside, for the quantitative assessment of pulmonary edema.

The Fetal Lamb Model of Congenital Diaphragmatic Hernia Shows Increased Lung Stiffness Using Shear Wave Elastography

The Fetal Lamb Model of Congenital Diaphragmatic Hernia Shows Increased Lung Stiffness Using Shear Wave Elastography

Minute ventilation/carbon dioxide production in chronic heart failure.

In chronic heart failure, minute ventilation (V'E) for a given carbon dioxide production (V'CO2 ) might be abnormally high during exercise due to increased dead space ventilation, lung stiffness, chemo- and metaboreflex sensitivity, early metabolic acidosis and abnormal pulmonary haemodynamics. The V'E versus V'CO2 relationship, analysed either as ratio or as slope, enables us to evaluate the causes and entity of the V'E/perfusion mismatch. Moreover, the V'E axis intercept, i.e. when V'CO2 is extrapolated to 0, embeds information on exercise-induced dead space changes, while the analysis of end-tidal and arterial CO2 pressures provides knowledge about reflex activities. The V'E versus V'CO2 relationship has a relevant prognostic power either alone or, better, when included within prognostic scores. The V'E versus V'CO2 slope is reported as an absolute number with a recognised cut-off prognostic value of 35, except for specific diseases such as hypertrophic cardiomyopathy and idiopathic cardiomyopathy, where a lower cut-off has been suggested. However, nowadays, it is more appropriate to report V'E versus V'CO2 slope as percentage of the predicted value, due to age and gender interferences. Relevant attention is needed in V'E versus V'CO2 analysis in the presence of heart failure comorbidities. Finally, V'E versus V'CO2 abnormalities are relevant targets for treatment in heart failure.

Nitric Oxide Releasing Hydrogel Nanoparticles Decreases Epithelial Cell Injuries Associated With Airway Reopening.

Acute respiratory distress syndrome (ARDS) is an acute inflammatory lung condition. It is characterized by disruption of gas exchange inside the alveoli, accumulation of protein edema, and an increase in lung stiffness. One major cause of ARDS is a lung infection, such as SARS-COV-2 infection. Lungs of ARDS patients need to be mechanically ventilated for airway reopening. Consequently, ventilation might damage delicate lung tissue leading to excess edema, known as ventilator-induced lung injury (VILI). Mortality of COVID-19 patients under VILI seems to be higher than non-COVID patients, necessitating effective preventative therapies. VILI occurs when small air bubbles form in the alveoli, injuring epithelial cells (EPC) due to shear stress. Nitric oxide (NO) inhalation was suggested as a therapy for ARDS, however, it was shown that it is not effective because of the extremely short half-life of NO. In this study, NO-releasing nanoparticles were produced and tested in an in vitro model, representing airways in the deep lung. Cellular injuries were quantified via fluorescent live/dead assay. Atomic force microscopy (AFM) was used to assess cell morphology. qRT-PCR was performed to assess the expression of inflammatory markers, specifically IL6 and CCL2. ELISA was performed to assess IL6 and confirm qRT-PCR results at the protein level. Finally, ROS levels were assessed in all groups. Here, we show that NO delivery via nanoparticles enhanced EPC survival and recovery, AFM measurements revealed that NO exposure affect cell morphology, while qRT-PCR demonstrated a significant downregulation in IL6 and CCL2 expression when treating the cells to NO both before and after shear exposure. ELISA results for IL6 confirmed qRT-PCR data. ROS experiment results support our findings from previous experiments. These findings demonstrate that NO-releasing nanoparticles can be used as an effective delivery approach of NO to deep lung to prevent/reduce ARDS associated inflammation and cell injuries. This information is particularly useful to treat severe ARDS due to COVID-19 infection. These nanoparticles will be useful when clinically administrated to COVID-19 patients to reduce the symptoms originating from lung distress.

Haemodynamic characteristics of COVID-19 patients with acute respiratory distress syndrome requiring mechanical ventilation. An invasive assessment using right heart catheterization.

AimsInterstitial pneumonia due to coronavirus disease 2019 (COVID‐19) is often complicated by severe respiratory failure. In addition to reduced lung compliance and ventilation/perfusion mismatch, a blunted hypoxic pulmonary vasoconstriction has been hypothesized, that could explain part of the peculiar pathophysiology of the COVID‐19 cardiorespiratory syndrome. However, no invasive haemodynamic characterization of COVID‐19 patients has been reported so far.Methods and resultsTwenty‐one mechanically‐ventilated COVID‐19 patients underwent right heart catheterization. Their data were compared both with those obtained from non‐mechanically ventilated paired control subjects matched for age, sex and body mass index, and with pooled data of 1937 patients with ‘typical’ acute respiratory distress syndrome (ARDS) from a systematic literature review. Cardiac index was higher in COVID‐19 patients than in controls [3.8 (2.7–4.5) vs. 2.4 (2.1–2.8) L/min/m2, P < 0.001], but slightly lower than in ARDS patients (P = 0.024). Intrapulmonary shunt and lung compliance were inversely related in COVID‐19 patients (r = −0.57, P = 0.011) and did not differ from ARDS patients. Despite this, pulmonary vascular resistance of COVID‐19 patients was normal, similar to that of control subjects [1.6 (1.1–2.5) vs. 1.6 (0.9–2.0) WU, P = 0.343], and lower than reported in ARDS patients (P < 0.01). Pulmonary hypertension was present in 76% of COVID‐19 patients and in 19% of control subjects (P < 0.001), and it was always post‐capillary. Pulmonary artery wedge pressure was higher in COVID‐19 than in ARDS patients, and inversely related to lung compliance (r = −0.46, P = 0.038).ConclusionsThe haemodynamic profile of COVID‐19 patients needing mechanical ventilation is characterized by combined cardiopulmonary alterations. Low pulmonary vascular resistance, coherent with a blunted hypoxic vasoconstriction, is associated with high cardiac output and post‐capillary pulmonary hypertension, that could eventually contribute to lung stiffness and promote a vicious circle between the lung and the heart.

Design and construction of a simplified, gas-driven, pressure-controlled emergency ventilator.

IntroductionDue to the COVID-19 crisis or any other mass casualty situation it might be necessary to give artificial ventilation to many affected patients. Contrarily, the worldwide availability of emergency ventilators is still a shortage, especially in developing countries.MethodsModes of artificial ventilation were compared and the most safe, easy to use, and lung protecting principle was optimized to fit all requirements of both emergency ventilation and cost-effective mass production.ResultsThe presented research results describe a simplified device for a pressure-controlled ventilation which works without electricity according to a known principle. Just pressurized gas and a patient connection is required. The device enables the control of basic ventilator parameters such as peak inspiratory pressure, positive end-expiratory pressure and the ventilation frequency. Further, the device is semiadaptive to the patient's lung stiffness and automatically maintains minute volume through frequency adjustment. The machine can be manufactured by turning, milling and drilling and needs purchased components with costs less than 100 USD. A sterilization and thus a reuse is possible.DiscussionThe presented development does not describe a ready-to-purchase ventilator, it rather outlines a refined working principle for emergency ventilation and its easiest methods of production with a minimum of requirements. The presented research aims on providing an open-source guideline for production of an emergency ventilator using worldwide available methods and thus should inspire local researchers to do a reverse engineering and eventually to put it into operation following country-specific regulations. For long-term ventilation exceeding emergency purposes, a monitoring of alarms for disconnection and violation of desired ventilator parameters should be established. The ventilator is limited to a fixed ratio between PIP and PEEP. Moreover, the ventilation frequency depends on two parameters, which needs some training. Nevertheless, the ventilator provides basic features to enable an emergency ventilation with minimal prerequisites.

Higher body mass index is associated with increased lung stiffness and less airway obstruction in individuals with asthma and fixed airflow obstruction.

Higher body mass index (BMI) is associated with less severe airway obstruction in older asthma patients with fixed airflow obstruction. This is potentially mediated through BMI-related mechanisms that increase lung stiffness (i.e. reduce lung compliance). https://bit.ly/3jBwCNy

Balanced Wnt/Dickkopf-1 signaling by mesenchymal vascular progenitor cells in the microvascular niche maintains distal lung structure and function.

The well-described Wnt inhibitor Dickkopf-1 (DKK1) plays a role in angiogenesis as well as in regulation of growth factor signaling cascades in pulmonary remodeling associated with chronic lung diseases (CLDs) including emphysema and fibrosis. However, the specific mechanisms by which DKK1 influences mesenchymal vascular progenitor cells (MVPCs), microvascular endothelial cells (MVECs), and smooth muscle cells (SMCs) within the microvascular niche have not been elucidated. In this study, we show that knockdown of DKK1 in Abcg2pos lung mouse adult tissue resident MVPCs alters lung stiffness, parenchymal collagen deposition, microvessel muscularization and density as well as loss of tissue structure in response to hypoxia exposure. To complement the in vivo mouse modeling, we also identified cell- or disease-specific responses to DKK1, in primary lung chronic obstructive pulmonary disease (COPD) MVPCs, COPD MVECs, and SMCs, supporting a paradoxical disease-specific response of cells to well-characterized factors. Cell responses to DKK1 were dose dependent and correlated with varying expressions of the DKK1 receptor, CKAP4. These data demonstrate that DKK1 expression is necessary to maintain the microvascular niche whereas its effects are context specific. They also highlight DKK1 as a regulatory candidate to understand the role of Wnt and DKK1 signaling between cells of the microvascular niche during tissue homeostasis and during the development of chronic lung diseases.

Abordaje hemodinámico y ventilatorio en pacientes con COVID-19.

The severe acute respiratory syndrome (SARS-Cov-2) is a clinical entity generated by this new virus a Coronavirus (COVID-19). Disease called COVID-19 (CoronaVIrus Disease 2019) by the World Health Organization. Its presentation is acute respiratory failure characterized by hyperinflation of the lung that leads to an increase in capillaries and epithelial permeability, with loss of ventilation of lung tissue and increases lung stiffness. These disturbances lead to imbalances between ventilation and perfusion ratio, which ultimately result in hypoxemia and impaired carbon dioxide clearance. For this review, a search of PubMed and Trip Database was performed. Due to the scarcity of publications, a specific search algorithm was not used. The objective is to review, the evidence and the recommendations of national and international experts, of the hemodynamic and ventilatory management of these patients.

Effects of New NSAID-CAI Hybrid Compounds in Inflammation and Lung Fibrosis.

Pulmonary fibrosis is a severe lung disease with progressive worsening of dyspnea, characterized by chronic inflammation and remodeling of lung parenchyma. Carbonic anhydrases are a family of zinc-metallo-enzymes that catalyze the reversible interconversion of carbon-dioxide and water to bicarbonate and protons. Carbonic Anhydrase Inhibitor (CAI) exhibited anti-inflammatory effects in animals with permanent-middle-cerebral artery occlusion, arthritis and neuropathic pain. The pharmacological profile of a new class of hybrid compounds constituted by a CAI connected to a Nonsteroidal-Anti-Inflammatory Drug (NSAID) was studied in the modulation of inflammation and fibrosis. In-vitro tests were performed to assess their effects on cyclo-oxygenase enzyme (COX)-1 and COX-2, namely inhibition of platelet aggregation and thromboxane B2 production in the human-platelet-rich plasma, and reduction of Prostaglandin-E2 production in lipopolysaccharide-treated-RAW-264.7 macrophage cell line. The activity of compound 3, one of the most active, was studied in a model of bleomycin-induced lung fibrosis in C57BL/6 mice. The hybrid compounds showed a higher potency in inhibiting PGE2 production, but not in modifying the platelet aggregation and the TXB2 production in comparison to the reference molecules, indicating an increased activity in COX-2 inhibition. In the in-vivo murine model, the compound 3 was more effective in decreasing inflammation, lung stiffness and oxidative stress in comparison to the reference drugs given alone or in association. In conclusion, these CAI-NSAID hybrid compounds are promising new anti-inflammatory drugs for the treatment of lung chronic inflammatory diseases.