A Cohort Study to Determine the Prevalence of Pulmonary Manifestations in Rheumatoid Arthritis

Background: Rheumatoid arthritis is an ailment that has an effect on the lungs in cases of pleural inflammation; it affects the lower as well as upper lung airways. Other effects of the disease can be seen in interstitial lung problems (parenchyma) and pulmonary vasculature. Aim: Evaluating the occurrence of pulmonary manifestations in RA patients was the objective of this study. Methods: An observatory method that was cross-section in nature was employed in this study which was held in the Rheumatology and Medicine department, Jinnah Medical and Dental College Karachi Pakistan for the one-year duration from June 2020 to June 2021. Eighty subjects were included in this study, and all of them underwent a general examination, their medical history was taken into account. Several lab tests were performed on the patients, ESR, BUN, CRP, HRCT, ALT, radiological investigations, and chest X-rays were included. Results: In this study42 percent of patients presented with pulmonary manifestations. About 45.70 percent of the patients presented with abnormalities in the spirometry test, 42.85 percent showed HRCT abnormalities. The HRCT scores vary with age, TJC (Tender Joint Count), ESR, and SJC.FEV, 1 HRCT, and FCV showed a negative correlation among each other. However other variables did not show any statistically significant correlation. Conclusion: RA showed the prevalence of pulmonary affection, and this can be observed in pulmonary and radiological functions. There was an associationof age, pulmonary functions, and ESR.

Metabolomics of lung microdissections reveals region- and sex-specific metabolic effects of acute naphthalene exposure in mice

Naphthalene is a ubiquitous environmental contaminant produced by combustion of fossil fuels and is a primary constituent of both mainstream and side stream tobacco smoke. Naphthalene elicits region-specific toxicity in airway club cells through cytochrome P450 (P450)-mediated bioactivation, resulting in depletion of glutathione and subsequent cytotoxicity. While effects of naphthalene in mice have been extensively studied, few experiments have characterized global metabolomic changes in the lung. In individual lung regions, we found metabolomic changes in microdissected mouse lung conducting airways and parenchyma obtained from animals sacrificed 2, 6, and 24 hours following naphthalene treatment. Data on 577 unique identified metabolites were acquired by accurate mass spectrometry-based assays focusing on lipidomics and non-targeted metabolomics of hydrophilic compounds. Statistical analyses revealed distinct metabolite profiles between the two major lung regions. In addition, the number and magnitude of statistically significant exposure-induced changes in metabolite abundance were different between lung airways and parenchyma for unsaturated lysophosphatidylcholines (LPCs), dipeptides, purines, pyrimidines, and amino acids. Importantly, temporal changes were found to be highly distinct for male and female mice, with males exhibiting predominant treatment-specific changes only at two hours post-exposure. In females, metabolomic changes persisted until six hours post-naphthalene treatment, which may explain the previously characterized higher susceptibility of female mice to naphthalene toxicity. In both males and females, treatment-specific changes corresponding to lung remodeling, oxidative stress response, and DNA damage were observed, which may provide insights into potential mechanisms contributing to the previously reported effects of naphthalene exposure in the lung.

Elevated CO 2 modulates airway contractility

Carbon dioxide (CO 2 ), a primary product of oxidative metabolism, can be sensed by eukaryotic cells eliciting unique responses via specific signalling pathways. Severe lung diseases such as chronic obstructive pulmonary disease are associated with hypoventilation that can lead to the elevation of CO 2 levels in lung tissues and the bloodstream (hypercapnia). However, the pathophysiological effects of hypercapnia on the lungs and specific lung cells are incompletely understood. We have recently reported using combined unbiased molecular approaches with studies in mice and cell culture systems on the mechanisms by which hypercapnia alters airway smooth muscle contractility. In this review, we provide a pathophysiological and mechanistic perspective on the effects of hypercapnia on the lung airways and discuss the recent understanding of high CO 2 modulation of the airway contractility.

The effects of pressure- versus volume-controlled ventilation on ventilator work of breathing

Background Measurement of work of breathing (WOB) during mechanical ventilation is essential to assess the status and progress of intensive care patients. Increasing ventilator WOB is known as a risk factor for ventilator-induced lung injury (VILI). In addition, the minimization of WOB is crucial to facilitate the weaning process. Several studies have assessed the effects of varying inspiratory flow waveforms on the patient’s WOB during assisted ventilation, but there are few studies on the different effect of inspiratory flow waveforms on ventilator WOB during controlled ventilation. Methods In this paper, we analyze the ventilator WOB, termed mechanical work (MW) for three common inspiratory flow waveforms both in normal subjects and COPD patients. We use Rohrer’s equation for the resistance of the endotracheal tube (ETT) and lung airways. The resistance of pulmonary and chest wall tissue are also considered. Then, the resistive MW required to overcome each component of the respiratory resistance is computed for square and sinusoidal waveforms in volume-controlled ventilation (VCV), and decelerating waveform of flow in pressure-controlled ventilation (PCV). Results The results indicate that under the constant I:E ratio, a square flow profile best minimizes the MW both in normal subjects and COPD patients. Furthermore, the large I:E ratio may be used to lower MW. The comparison of results shows that ETT and lung airways have the main contribution to resistive MW in normals and COPDs, respectively. Conclusion These findings support that for lowering the MW especially in patients with obstructive lung diseases, flow with square waveforms in VCV, are more favorable than decelerating waveform of flow in PCV. Our analysis suggests the square profile is the best choice from the viewpoint of less MW.

Thalidomide-Revisited: Are COVID-19 Patients Going to be the Latest Victims of Yet Another Theoretical Drug-Repurposing?

The new pandemic coronavirus disease 2019 (COVID-19) is a worldwide threatening health issue. Early progression of this disease starts in the lung airways with an exaggerated inflammation, triggered by the viral infection and characterized by a “cytokine storm” that can lead to lethal lung injuries. In the absence of an effective anti-viral molecule and until the formulation of a successful vaccine, anti-inflammatory drugs might offer a complementary tool for controlling the associated complications and thus decreasing the subsequent fatalities. Drug repurposing for several molecules has emerged as a rapid temporary solution for COVID-19. Among these drugs, Thalidomide, a historically emblematic controversial molecule that harbors an FDA approval for treating Erythema Nodosum Leprosum (ENL) and multiple myeloma (MM). Based on only one-case report of positive outcomes in a patient treated amongst others with Thalidomide, two clinical trials on the efficacy and safety of Thalidomide in treating severe respiratory complications in COVID-19 patients were registered. Conversely, the absence of any substantial, promising evidence on Thalidomide usage in that context along with the discontinued studies on the efficiency of this drug in similar pulmonary diseases might cause a significant obstacle for carrying on clinical studies. In this review, we will discuss the theoretical effectiveness of this drug in attenuating inflammatory complications that are encountered in patients with COVID-19 while pinpointing the lack of evidence that is needed to move forward with this drug.

Respiratory changes during adaptation to stress induced by movement restriction in rabbits

Background Confinement inside a restricted space causing movement restriction is a stressful condition, potentially leading to spontaneous changes of respiratory parameters that are expected to return to normal values as the stress subsides. Barometric plethysmography is a non-invasive method to study surrogates of pulmonary mechanics in conscious animals enclosed into a plexiglass chamber. This chamber greatly restricts the animal movements but does not cause its immobilization. Methods Respiratory parameters from six rabbits were recorded during 90 min/day for 5 days while the animal was confined inside a plethysmographic chamber. Modifications of respiratory parameters were evaluated by dividing the total length of the recording in three 30-min periods. Results During the 90-min recording, enhanced pause (Penh, a lung resistance surrogate) showed a decreasing trend, coinciding with a decline of the mid-expiratory flow (an airway obstruction surrogate), and time of braking (an end-inspiratory glottis closure surrogate). Respiratory frequency increased from 346 to 363 breaths/min, coinciding with a progressive decline of tidal volume and minute ventilation. Because rabbit responses to stressful situations are predominantly parasympathetic in nature, an increased parasympathetic tone during the first minutes of confinement might explain the initially augmented lung, airways and glottis resistances, and these, in turn, could be responsible for the low initial respiratory frequency. Subsequent changes of these variables probably reflect progressively lower level of stress due to adaptation to the new environment. This pattern did not change in the 5 days studied. Conclusions We concluded that respiratory parameters in rabbits display subtle changes during the first 90 min of movement restriction, probably driven by an initially augmented parasympathetic tone due to stress, with subsequent normalization as stress diminished due to adaptation to the new environment.

Derivation of Airway Basal Stem Cells from Human Pluripotent Stem Cells

SummaryThe derivation of self-renewing tissue-specific stem cells from human induced pluripotent stem cells (iPSCs) would shorten the time needed to engineer mature cell types in vitro and would have broad reaching implications for the field of regenerative medicine. Here we report the directed differentiation of human iPSCs into putative airway basal cells (“iBCs”), a population resembling the epithelial stem cell of lung airways. Using a dual fluorescent reporter system (NKX2-1GFP;TP63tdTomato) we track and purify these cells over time, as they first emerge from iPSC-derived foregut endoderm as developmentally immature NKX2-1GFP+ lung progenitors which then augment a TP63 program during subsequent proximal airway epithelial patterning. These cells clonally proliferate, initially as NKX2-1GFP+/TP63tdTomato+ immature airway progenitors that lack expression of the adult basal cell surface marker NGFR. However, in response to primary basal cell medium, NKX2-1GFP+/ TP63tdTomato+ cells upregulate NGFR and display the molecular and functional phenotype of airway basal stem cells, including the capacity to clonally self-renew or undergo multilineage ciliated and secretory epithelial differentiation in air-liquid interface cultures. iBCs and their differentiated progeny recapitulate several fundamental physiologic features of normal primary airway epithelial cells and model perturbations that characterize acquired and genetic airway diseases. In an asthma model of mucus metaplasia, the inflammatory cytokine IL-13 induced an increase in MUC5AC+ cells similar to primary cells. CFTR-dependent chloride flux in airway epithelium generated from cystic fibrosis iBCs or their syngeneic CFTR-corrected controls exhibited a pattern consistent with the flux measured in primary diseased and normal human airway epithelium, respectively. Finally, multiciliated cells generated from an individual with primary ciliary dyskinesia recapitulated the ciliary beat and ultrastructural defects observed in the donor. Thus, we demonstrate the successful de novo generation of a tissue-resident stem cell-like population in vitro from iPSCs, an approach which should facilitate disease modeling and future regenerative therapies for a variety of diseases affecting the lung airways.

Targeted Drug Delivery of Magnetic Nano-Particle in the Specific Lung Region

Aerosolized drug inhalation plays an important role in the treatment of respiratory diseases. All of the published in silico, in vivo, and in vitro studies have improved the knowledge of aerosol delivery in the human respiratory system. However, aerosolized magnetic nano-particle (MNP) transport and deposition (TD) for the specific position of the human lung are still unavailable in the literature. Therefore, this study is aimed to provide an understanding of the magnetic nano-particle TD in the targeted region by imposing an external magnetic field for the development of future therapeutics. Uniform aerosolized nano-particle TD in the specific position of the lung airways will be modelled by adopting turbulence k–ω low Reynolds number simulation. The Euler–Lagrange (E–L) approach and the magneto hydrodynamics (MHD) model are incorporated in the ANSYS fluent (18.0) solver to investigate the targeted nano-particle TD. The human physical activity conditions of sleeping, resting, light activity and fast breathing are considered in this study. The aerosolized drug particles are navigated to the targeted position under the influence of external magnetic force (EMF), which is applied in two different positions of the two-generation lung airways. A numerical particle tracing model is also developed to predict the magnetic drug targeting behavior in the lung. The numerical results reveal that nano-particle deposition efficiency (DE) in two different magnetic field position is different for various physical activities, which could be helpful for targeted drug delivery to a specific region of the lung after extensive clinical trials. This process will also be cost-effective and will minimize unwanted side effects due to systemic drug distribution in the lung.