Predictors of Pulmonary Hypertension and Right Ventricular Dysfunction in Patients with Hypersensitivity Pneumonitis.

BACKGROUND: Hypersensitivity pneumonitis (HP) is an interstitial lung disease (ILD) that occurs in susceptible individuals in response to various inhaled antigens. The fibrotic phenotype of HP is characterized by disease progression and can lead to pulmonary hypertension (PH). The aim of this study was to estimate the prevalence of PH and to identify predictors of PH in patients with chronic HP. METHODS: We conducted an observational longitudinal study that included 85 patients with an established diagnosis of HP. Clinical examination, quality of life questionnaires, high-resolution computed tomography (HRCT) of the chest, arterial blood gases analyses, six-minute walking test (6-MWT), pulmonary function tests, and echocardiography were performed. RESULTS: Patients were divided into groups with fibrotic (71.8%) and nonfibrotic phenotype (28.2%). PH was detected in 41 (48.2%) patients. Patients with PH had the predominant fibrotic phenotype of HP, were older, more symptomatic, and had a higher FVC/DLco ratio. The most significant predictors of PH were CT signs of fibrosis, finger clubbing, FVC/DLco, decreased distance, and SpO2 at the end of 6-MWT, as well as the presence of cardiovascular diseases. CONCLUSIONS: PH is a common condition in patients with chronic HP, especially with the fibrotic phenotype. Early detection of the PH predictors is necessary for the timely diagnosis of this complication of HP.

Predictors of Progression and Mortality in Patients with Chronic Hypersensitivity Pneumonitis: Retrospective Analysis of Registry of Fibrosing Interstitial Lung Diseases.

Hypersensitivity pneumonitis (HP) is an interstitial lung disease (ILD) resulting from an immune-mediated response in susceptible and sensitized individuals to a large variety of inhaled antigens. Chronic HP with a fibrotic phenotype is characterized by disease progression and a dismal prognosis. The aim of this study was to identify predictors of progression and mortality in patients with chronic HP in real clinical practice. MATERIALS AND METHODS: This retrospective, multicenter, observational study used data from a registry of 1355 patients with fibrosing ILDs. The study included 292 patients diagnosed with chronic HP based on the conclusion of a multidisciplinary discussion (MDD). RESULTS: The patients were divided into groups with progressive (92 (30.3%) patients) and nonprogressive pulmonary fibrosis (200 (69.7%) patients). The most significant predictors of adverse outcomes were a DLco < 50% predicted, an SpO2 at the end of a six-minute walk test (6-MWT) < 85%, and a GAP score ≥ 4 points. CONCLUSION: Pulmonary fibrosis and a progressive fibrotic phenotype are common in patients with chronic HP. Early detection of the predictors of an adverse prognosis of chronic HP is necessary for the timely initiation of antifibrotic therapy.

Role of mast cells in the pathogenesis of severe lung damage in COVID-19 patients.

BACKGROUND: There is still insufficient knowledge with regard to the potential involvement of mast cells (MCs) and their mediators in the pathology of coronavirus disease-2019 (COVID-19). Therefore, our study aimed to investigate the role of MCs, their activation and protease profiles in the pathogenesis of early and late lung damage in COVID-19 patients. METHODS: Formalin-fixed and paraffin embedded lung specimens from 30 patients who died from COVID-19 and 9 controls were used for histological detection of MCs and their proteases (tryptase, chymase) followed by morphometric quantification. RESULTS: Our results demonstrated increased numbers of MCs at early stage and further augmentation of MCs number during the late stage of alveolar damage in COVID-19 patients, as compared to the control group. Importantly, the percentage of degranulated (activated) MCs was higher during both stages of alveolar lesions in comparison to the controls. While there was no prominent alteration in the profile of tryptase-positive MCs, our data revealed a significant elevation in the number of chymase-positive MCs in the lungs of COVID-19 patients, compared to the controls. CONCLUSIONS: MCs are characterized by dysregulated accumulation and increased activation in the lungs of patients suffering from COVID-19. However, future profound studies are needed for precise analysis of the role of these immune cells in the context of novel coronavirus disease.

Anti-IL-17 monoclonal antibodies in hospitalized patients with severe COVID-19: A pilot study.

BACKGROUND: One of the main pathophysiological mechanisms underlying the severe course of COVID-19 is the hyper-inflammatory syndrome associated with progressive damage of lung tissue and multi-organ dysfunction. IL-17 has been suggested to be involved in hyper-inflammatory syndrome. OBJECTIVE: To evaluate the efficacy and safety of the IL-17 inhibitor netakimab in patients with severe COVID-19. STUDY DESIGN: In our retrospective case-control study we evaluated the efficacy of netakimab in hospitalized patients with severe COVID-19 outside the intensive care unit (ICU). Patients in the experimental group were treated with standard of care therapy and netakimab at a dose of 120 mg subcutaneously. RESULTS: 171 patients with severe COVID-19 were enrolled in our study, and 88 of them received netakimab. On the 3 day of therapy, body temperature, SpO2/FiO2, NEWS2 score, and CRP improved significantly in the netakimab group compared to the control group. Other clinical outcomes such as transfer to ICU (11.4% vs 9.6%), need for mechanical ventilation (10.2% vs 9.6%), 28-day mortality (10.2% vs 8.4%), did not differ between the groups. CONCLUSION: In hospitalized patients with severe COVID-19, anti-IL-17 therapy might mitigate the inflammatory response and improve oxygenation, but do not affect the need for mechanical ventilation and mortality.

Doxorubicin delivery systems based on doped CaCO3 cores and polyanion drug conjugates.

In order to prolong the release and reduce the toxicity of anticancer drug - doxorubicin (DOX), delivery systems (DS) using different polyanions have been developed. Structural (size, morphological stability) and functional (encapsulation efficiency, DOX release) characteristics of three types of DS are compared: CaCO3 porous vaterites doped with polyanions by co-precipitation and coating techniques, and DOX-polyanion conjugates. Using scanning electron microscopy (SEM) and energy dispersive X-ray spectroscopy (EDS), it was shown that the doping enhances the morphological stability of CaCO3-based DS during the DOC loading. Doping of CaCO3 cores by co-precipitation reduces its sizes (up to 1 µm) and DOX encapsulation efficiency. Polyanion-coated CaCO3 cores and polyanion drug conjugates show about 98 w/w% DOX encapsulation. For the first time, it was shown that the release of DOX from developed DS into human blood plasma is more intense (from 1.3 to 3.0 times for different DS) than into model tumour environment.

Two-level delivery systems based on CaCO3 cores for oral administration of therapeutic peptides.

Two-level systems for oral delivery of therapeutic peptides were developed; the carriers consist of CaCO3 cores included into alginate granules. Such systems were first used for the delivery of low molecular weight drugs. It was shown that efficiency of encapsulation of peptides depends on their pI value, hydrophobicity, characteristics of the compounds used for doping CaCO3 cores, their surface potential and the techniques employed for loading peptides into the first-level carriers. Doping CaCO3 cores with dextran sulphate save their viability compared to the pristine CaCO3 cores, but ensures delivery of the desired quantity of peptide when using a smaller amount of delivery systems. Introducing the inhibitor of peptidases leads to an increase in the concentration of peptide in rat blood after intragastric administration of the developed delivery systems. Scanning electron microscopy and energy-dispersive X-ray spectroscopy demonstrated the presence of fragments of destructed first-level carriers in blood and plasma of experimental animals.

Two-level delivery systems for oral administration of peptides and proteins based on spore capsules of Lycopodium clavatum.

Two-level delivery systems (DSs) for oral administration of therapeutic proteins and peptides were developed. The first level consists of outer walls of Lycopodium clavatum spores (sporopollenin exine capsules, SECs) with included target objects; the alginate microgranules serve as the second (outer) level. Alginate (a pH-dependent natural polymer) protects peptides from gastric acidity and enzyme exposure and provides slow release of target objects in an alkaline intestinal medium. Introducing ovomucoid (a peptidase inhibitor) into alginate coatings prevents enzymatic hydrolysis of peptide objects in the intestinal medium. The elemental composition of spores and SECs was controlled using energy-dispersion spectroscopy and combustion analysis; their morphology was visualized by SEM. The efficiencies of different methods of SEC loading were compared. It was demonstrated that the load value was controlled by molecular mass and the value of the isoelectric point of target objects. A comparison of peptide in vitro release profiles from DSs of various structures into simulated gastric and intestinal fluids was carried out. The mechanism of peptide release from two-level DSs was suggested. SECs were found in rat blood after intragastric administration of the two-level DSs. Time profiles of therapeutic peptide release were obtained in vivo.

Alginate-containing systems for oral delivery of superoxide dismutase. Comparison of various configurations and their properties.

The regularities of release of therapeutic antioxidant enzyme superoxide dismutase (SOD) from various alginate-based delivery systems (DS) into simulated gastric and intestinal fluids were determined. The following systems were used: Ca-alginate granules (AG) prepared by various methods, porous carbonate cores with multilayer polyelectrolyte coating as well as the new two-level DS (Ca-AG containing carbonate cores loaded with proteins). The influence of the method of granule preparation, composition of gelation bath and ionic composition of the simulated fluids on release profiles of the protein from different DS was revealed. SEM images demonstrated changes in DS structures in various simulated fluids. The correlation between these changes and in vitro protein release was shown. The comparison of enzymatic activity of SOD encapsulated in DS of various configurations (including the systems containing different peptidase inhibitors) was made. The efficiency of protection of SOD activity in simulated intestinal fluid with trypsin was demonstrated.

Annulated dinuclear metal-free and Zn(II) phthalocyanines: photophysical studies and quantum mechanical calculations.

The results of steady-state and time-resolved absorption and fluorescence experiments as well as quantum mechanical density functional theory (DFT) calculations of metal-free and Zn(II) mononuclear and dinuclear (sharing a common benzene ring) phthalocyanines are presented. A detailed comparison between measured and calculated absorption spectra of all compounds is done, showing a good agreement between theory and experiment. The NH tautomerization for phthalocyanines with an extended pi-electron system was shown for the first time at room temperature. The photophysical properties of all possible NH tautomers of metal-free dinuclear Pc have been fully characterized. In the first tautomer, Pc(parallel), both pairs of hydrogen atoms are parallel to the connection line of two Pc units. The maximum of the lowest-energy Q absorption band, lambda abs, in Pc(parallel) is located at 832 nm, whereas the spectral position of the fluorescence maximum lies at lambdafl=837 nm. The second NH tautomer, Pc(perpendicular) (lambdaabs=853 nm, lambdafl=860 nm), presents the two pairs of hydrogen atoms perpendicularly orientated to the covalent axis, and the third one, Pc(mix) (lambdaabs=864 nm, lambdafl=872 nm), contributing in a minor extend to the absorption and fluorescence spectra of the metal-free dinuclear phthalocyanine, has one perpendicular and one parallel pair of hydrogen atoms. Obviously, only one configuration exists in the case of the Zn(II)-containing dinuclear phthalocyanine (lambdaabs=845 nm, lambdafl=852 nm).

Near-infrared absorbing ligand-oxidized dinuclear phthalocyanines.

Ligand-oxidized annulated dinuclear phthalocyanine zinc(II) and lithium(I) complexes absorbing in the NIR region (lambda=1000-2200 nm) with high extinction coefficients are described. Analogous mononuclear Pc complexes were used for comparison. The oxidized Pcs were characterized in solution by electronic absorption, EPR and NMR spectra. The NIR transitions were explained by using MO diagrams calculated semiempirically. The reversible oxidation behavior of the phthalocyanine complexes was also estimated by cyclic voltammetry. These new extremely long wavelength absorbing phthalocyanines are interesting as materials with new electronic properties.

Synthesis and photophysical properties of annulated dinuclear and trinuclear phthalocyanines.

Metal-free mononuclear, dinuclear and trinuclear phthalocyanines were prepared by a mixed cyclotetramerisation of a 1,2,4,5-tetracyanobenzene derivative and 4,5-bis(2,6-dimethylphenoxy)phthalonitrile. For the first time, a pi-electron-conjugated trinuclear phthalocyanine was synthesised with phthalocyanine units connected by common annulated benzene rings. The Q band of the trinuclear compound in solution occurs at lambda = 944 nm whereas those of the dinuclear and mononuclear compounds are at lambda = 853/830 and 701/664 nm, respectively. Fluorescence quantum yields, fluorescence lifetimes and singlet-oxygen quantum yields of the compounds were determined.