Novel coronavirus SARS-CoV-2 (Covid-19) dynamics inside the human body.

A knowledge-based cybernetic framework model representing the dynamics of SARS-CoV-2 inside the human body has been studied analytically and in silico to explore the pathophysiologic regulations. The following modeling methodology was developed as a platform to introduce a predictive tool supporting a therapeutic approach to Covid-19 disease. A time-dependent nonlinear system of ordinary differential equations model was constructed involving type-I cells, type-II cells, SARS-CoV-2 virus, inflammatory mediators, interleukins along with host pulmonary gas exchange rate, thermostat control, and mean pressure difference. This formalism introduced about 17 unknown parameters. Estimating these unknown parameters requires a mathematical association with the in vivo sparse data and the dynamic sensitivities of the model. The cybernetic model can simulate a dynamic response to the reduced pulmonary alveolar gas exchange rate, thermostat control, and mean pressure difference under a very critical condition based on equilibrium (steady state) values of the inflammatory mediators and system parameters. In silico analysis of the current cybernetical approach with system dynamical modeling can provide an intellectual framework to help experimentalists identify more active therapeutic approaches.

Influence of repeated maximal exercise testing on biomarkers and fatigue in sarcoidosis.

Fatigue in the immune mediated inflammatory disease sarcoidosis is thought to be associated with impaired exercise tolerance. This prospective study assessed fatigue and recuperative capacity after repeated exercise, and examined whether changing concentrations in biomarkers upon exercise are associated with fatigue. Twenty sarcoidosis patients and 10 healthy volunteers performed maximal cardiopulmonary exercise tests on two successive days. Concentrations of cytokines, stress hormones, ACE and CK were assessed before and after the two exercise tests, and 3 days thereafter. All participants completed a sleep diary. Severely fatigued patients showed significant lower VO2 max (p=0.038, p=0.022) and maximal workload (p=0.034, p=0.028) on both exercise tests compared to healthy controls. No impairment of maximal exercise testing was demonstrated during the second cycling test in any group. Fatigue was not correlated with changes in concentrations of biomarkers upon exercise. Severely fatigued patients rated both tests as significantly more fatiguing, and reported significant lower mean subjective night sleeping time during the testing period. Fatigue in sarcoidosis patients cannot be objectified by reduction of exercise capacity after repeated maximal exercise testing, and is not correlated with significant changes in biomarkers. Severe fatigue is only and consistently featured by patient reported outcomes.

Potent inflammatory cytokine response following lung volume recruitment maneuvers with HFOV in pediatric acute respiratory distress syndrome.

OBJECTIVE: Lung volume recruitment maneuver (LVRM) may improve gas exchange but inflating the lungs to nearly vital capacity may cause further lung injuries. Our aim was to determine the potent inflammatory cytokine response following lung volume recruitment (LVRM) with high frequency oscillator ventilation (HFOV) in pediatric acute respiratory distress syndrome (ARDS). METHODS: We prospectively recruited pediatric patients (age >1 month - <15 year old) with a diagnosis of ARDS within 72 hrs of PICU admission. They underwent the LVRM protocol combined with HFOV. Any enrolled subject who had a 20% improvement in PaO2/FiO2 (PF ratio) 1 hr after the LVRM we classified as a responder. Baseline clinical data were recorded. Blood was also drawn at baseline, 1 & 24 hrs after LVRM and kept for further sICAM-1, IL-6 & IL-8 analysis. RESULTS: Eighteen children with ARDS were enrolled. Their mean age was at 6.8 +/- 6.1 years (mean +/- SD). The initial oxygen index (iOI) was at 26.8 +/- 17.8 (11.5-84.9). There was no significant differences in sICAM-1, IL-6 and IL-8 levels at baseline; (34 +/- 17.5, 121.7 +/- 115.15, 601.5 +/- 675 pg/ml); 1 hr (39.6 +/- 28.7, 99.8 +/- 75.5, 617.4 +/- 692.5 pg/ml) and at 24 hrs (44.23 +/- 34.4, 109.4 +/- 63.9, 737.6 +/- 922.3 pg/ml) following LVRMs, respectively. However, there was significant difference in the elevation of sICAM-1 levels (%change) from baseline in responders (-1.8 +/- 12.2%) vs. non-responders (47.65 +/- 43.5%) at 1 hr. Additionally, sICAM-1 levels were also significantly higher at baseline, 1 hr and 24 hrs in non-survivors as compared with survivors. CONCLUSION: There was no significant elevation of potent inflammatory cytokines that may indicate further lung injuries in the majority of our patients. However, there was significant elevation of sICAM-1 levels in non-responders and in those who did not survive that may indicate more lung injuries in these individuals.

Effect of tacrolimus on endotoxin-induced lung injury in sheep.

Since tacrolimus (FK-506) is known to suppress the proliferation and generation of T cells and to inhibit the production of T cell derived cytokines, we examined the effect of FK-506 on endotoxin-induced lung injury. We administered FK-506 (0.1 mg/kg) intravenously before the infusion of endotoxin (1 microgram/kg) into conscious sheep. We measured pulmonary hemodynamics, lung fluid balance, circulating leukocyte count and arterial blood gas tensions. The increase in pulmonary arterial pressure was significantly attenuated by FK-506 during the late period (3-5 h after endotoxin). Arterial oxygen gas tension was significantly higher in the FK-506 treated sheep during this phase. However, no significant differences were observed in lung lymph balance and circulating leukocyte count between the endotoxin alone group and the FK-506 treated group. These findings suggest that FK-506 may improve gas exchange in acute lung injury although there is an increased pulmonary vascular leakage. It is probable that FK-506 may have a beneficial potential on endotoxin-induced lung injury in sheep.

Continuous lateral rotational therapy and systemic inflammatory response in posttraumatic acute lung injury: results from a prospective randomised study.

BACKGROUND: The incidence of posttraumatic acute lung injury is high and may result in increased mortality. Changes in the body position are additional measures to improve pulmonary gas exchange and to prevent pulmonary complications. We investigated the effect of a continuous lateral rotational therapy (CLRT) on the inflammatory response in patients with posttraumatic lung failure. METHODS: After admission to the intensive care unit (ICU) and after randomisation, 13 patients were placed in a special motor-driven bed and CLRT was performed for 5 days. In the control group (n=14), patients were positioned conventionally. Samples from blood and from broncho-alveolar lavage fluid (BAL) were collected in both groups before study began and on day 5. The levels of cytokines (Tumour Necrosis Factor, Interleukin 6, Interleukin 8 or Intercellular Adhesion Molecule-1) were assessed and haemodynamic, pulmonary, and laboratory values were documented. RESULTS: On day 5, no significant differences were found in cytokine levels between groups, but a significant decrease in IL-8 (p<0.01) and TNF-α (p<0.05) serum levels and an increase in IL-8 BAL levels was found in the CLRT-group, but not for conventionally managed patients. In general cytokine BAL levels tended to be increased in both groups, but more pronounced during CLRT. Daily assessment of the severity of disease (SAPS-II, SOFA) was significantly reduced in the study group on days 2-4 (p<0.05) in comparison to control group. CONCLUSIONS: CLRT may attenuate the inflammatory response to posttraumatic acute lung injury. The exact mechanism of such an effect is unknown.

[Hematopoietic stem cells and immune status of subjects with different hypoxic tolerance].

Intermittent hypoxia treatment (IHT) is gaining attention as a clinical modality due to its capacity to protect cells, tissues, organs, and the whole organism from more intense and/or sustained hypoxia, ischemia and other stresses, to enhance physical and mental capacity. Circulating hematopoietic stem and progenitor cells (HSPC) play an important role in immune response to hypoxia ensuring tissue reparation processes, formation of all types of blood cells etc. There exist considerable individual differences in the capability to mobilize HSPC. This study was designed to compare the effects of IHT on HSPC, various factors of natural resistance and main humoral and cellular components of adaptive immunity in peripheral blood of subjects with normal and reduced tolerance to hypoxic load. Ten healthy male volunteers (age 30,9 +/- 0,6 y.o.) participated in the study and were divided into two groups with reduced (RT, 5 subjects) and normal (NT, 5 subjects) hypoxic tolerance. Criterion for reduced hypoxic tolerance detection was the exceeding deviation of arterial blood pressure, minute ventilation, SaO2 and/or pathological changes in ECG during sustained hypoxia test (breathing with 10% oxygen, 10 min). All subjects were studied before and after a 14 day IHT program consisting of four 5 min bouts/d of breathing 10% O2, with intervening 5 min room air exposures. Immunofluorescence detected HSPCs as CD45+CD34+ cells in peripheral blood. Phagocytic and bactericidal activities of neutrophils, circulating immunoglobulins (IgM, IgG, IgA), immune complexes, complement, and cytokines (EPO, TNF-alpha, IL-4, IFN-gamma) were measured. It was shown that NT subjects had higher hemoglobin and erythrocytes level, hematocrit and physical working capacity, but leukocytes, lymphocytes, CD8+-cells contents and level of IgA were lower than in RT. These differences were preserved after IHT course. CD45+34+cells content was the same in both groups before IHT, but RT subjects demonstrated twice decrease in HSPCs content after IHT as opposed to NT who did not show distinct reactions. A decrease in HSPCs is probably associated with the change of their migration capacity. However, it remains unclear whether there is an inhibition of HSPCs migration into circulation or an activation ofHSPCs escape from circulation. In both cases tissues could accumulate more HSPCs which in turn could enhance hematopoiesis and general regenerative potential. RT group also had lower complement, induced and reserve bactericidal activities of neutrophils which were significantly increased after IHT reaching the level of NT. The level of cytokines EPO, TNF-alpha and IFN-gamma did not differ in both groups before IHT but considerably reduced level of IL-4 was registered in RN patients. IHT sharply lowered pro-inflammatory cytokine TNF-alpha in both groups, significantly increased IL-4 in RT subjects; increasing behavior of IFN-gamma was observed in both groups. EPO was not affected considerably during the study. The findings support the potential for eventual application of IHT for immunotherapy, especially for patients with reduced hypoxic tolerance.

Airway smooth muscle cells respond directly to inhaled environmental factors.

A misled or overreacting immune response is assumed to be the major cause of the most prevalent chronic inflammatory lung diseases, asthma and chronic obstructive pulmonary disease (COPD). The contribution of tissue forming cells, especially of airway smooth muscle cells, to the pathologies of both diseases has only recently attracted some attention. New studies in childhood asthma and a rhesus monkey model strongly suggest a central role of the airway smooth muscle cells in lung development, structure, function and response to environmental factors. Airway smooth muscle cells express and respond to activation of IgE receptors. In addition, airway smooth muscle cells recognise and respond to environmental factors, including allergens and dust, via mechanisms that are independent of the immune system such as PAR2 or calreticulin. Interestingly, these changes occur not on the level of gene activity but on the level of protein synthesis. The reason why these temporary changes become chronic in asthma and COPD remains to be studied.

Pulmonary gas exchange response following allergen challenge in patients with allergic asthma.

Pulmonary gas exchange was studied in 8 patients with allergic asthma before and after allergen challenge. Ventilation-perfusion relationships were assessed by the multiple inert gas elimination technique and forced expiratory flow by conventional spirometry. Measurements were made before, 7-8 minutes, and 0.5, 2.5 and 5 hours after challenge. During baseline conditions all patients showed normal forced expiratory flow (FEV1 3.9 +/- 0.77 (SD) l) and gas exchange expressed as the dispersion of pulmonary blood flow, log SDQ (0.35 +/- 0.08), (one of the common descriptors of ventilation-perfusion (VA/Q) inequality). Immediately after challenge there were significant decreases in FEV1 (to 2.3 +/- 0.75 l) and arterial PO2 (from 13.1 +/- 0.9 to 9.5 +/- 1.2 kPa). The developed ventilation-perfusion inequalities were similar to those found in other asthma studies, i.e. mainly a broad (log SDQ increased to 0.73 +/- 0.30) and sometimes bimodal distribution of the perfusion. Thirty minutes after challenge FEV1 significantly improved to 3.2 +/- 1.18 l while log SDQ remained high (0.71 +/- 0.32). Two and a half hours after challenge log SDQ was reduced and almost normalized to 0.38 +/- 0.07. Five patients developed a late phase reaction with decreasing flow rates after 5 hours. Three of these patients also showed increased log SDQ. There was no clear relationship between gas exchange mismatch and reduced forced expiratory flow. The results support the hypothesis that reduced expiratory flow and gas exchange impairment are caused by different pathophysiological mechanisms.

Pulmonary defense mechanisms.

The airways and gas-exchanging surfaces of the lung are an important interface between the host and the external environment. Potentially injurious particulates and gases continuously impact on this extensive epithelial surface. The pulmonary defense apparatus, which uses anatomic barriers, aerodynamics, soluble factors and a multitude of cellular processes, protects the airways and the alveolar surfaces so that gas exchange between the host and the environment can occur.

The effects of body fat on pulmonary function and gas exchange in cynomolgus monkeys.

Obesity adversely affects lung function in humans often reducing arterial blood oxygenation. To determine if obesity adversely affects lung function in cynomolgus monkeys, which is a species that is often used for pulmonary research, pulmonary mechanics, ventilation, functional residual capacity (FRC), and arterial blood gases were measured using spontaneous respiration and on mechanical ventilation with room air or 100% O(2). Body fat percentage was measured by dual energy X-ray absorption. Blood leptin levels were measured by radioimmune assay. Obese monkeys breathed faster with lower tidal volume, but pulmonary resistance and dynamic lung compliance did not change with body fat. FRC and blood leptin were, respectively, negatively and positively correlated with percent body fat. FRC correlated moderately with ventilatory parameters and strongly with arterial oxygen tension, alveolar-arterial oxygen difference and venous admixture. Therefore, obesity in cynomolgus monkeys had marked, deleterious effects on FRC, ventilation and arterial oxygenation. Obesity may be an important confounding variable in lung function studies in primates.

Prostacyclin is neither sufficient alone nor necessary to cause pulmonary dysfunction: results from infusions of prostacyclin and antiprostacyclin antibody in porcine septic shock.

OBJECTIVE: This study evaluated whether prostacyclin is a necessary mediator of inflammation in graded bacteremia or is sufficient alone in pathophysiologic concentrations to cause the pulmonary derangement of bacteremic shock. DESIGN: Experimental. SETTING: Laboratory. SUBJECTS: Twenty-three anesthetized adult swine. INTERVENSIONS: Swine were studied in four groups for 4 hrs: a) an anesthesia control group (n = 6); b) a septic control group (n = 6), in which 1010/mL Aeromonas hydrophila was infused intravenously at 0.2 mL.kg-1.hr-1 and increased to 4.0 mL.kg-1.hr-1 over 3 hrs; c) a prostacyclin infusion group (n = 6), which received prostacyclin infusion to match septic control plasma concentrationsclm without bacteremia; and d) an antiprostacyclin antibody group (n = 5), which received continuous Aeromonas hydrophila infusion plus antiprostacyclin antibody infusion. MEASUREMENTS AND MAIN RESULTS: Pulmonary hemodynamics, arterial blood gases, and plasma concentrations of arachidonate metabolites were measured hourly over a 4-hr period. In the septic control group and antiprostacyclin antibody group, elevated pulmonary vascular resistance index and pulmonary artery pressure with decreased Pao2, as well as lower pH, were documented after 1 and 3 hrs of graded bacteremia compared with the anesthesia control group and prostacyclin infusion group (p <.05). Thromboxane B2 concentration increased significantly in all groups during septic shock. In the antiprostacyclin antibody group, leukotriene B4 increased immediately after starting antiprostacyclin antibody infusion and reached significance at 3 hrs compared with the septic control group (p <.05). The prostacyclin infusion group had consistently lower concentrations of leukotrienes C4, D4, and E4 than all other groups. CONCLUSIONS: Prostacyclin does not mediate blood gas changes, alterations of pulmonary hemodynamics, or platelet abnormalities in porcine septic shock, because antiprostacyclin antibody infusion did not change the pulmonary hypertension and hypoxemia, and infusion of prostacyclin to pathophysiologic blood concentrations did not reproduce such changes. Antiprostacyclin blockade during bacteremia significantly increased concentrations of leukotrienes C4, D4, and E4 and leukotriene B4, whereas prostacyclin infusion suppressed concentrations of leukotrienes C4, D4, and E4, suggesting that endogenous prostacyclin may blunt leukotriene release.

Acute reversible hypoxemia in systemic lupus erythematosus.

OBJECTIVE: To determine the frequency of unexplained reversible hypoxemia in patients with systemic lupus erythematosus and to assess the relation between hypoxemia and elevated plasma levels of complement split products. DESIGN: Cohort study. SETTING: Inpatient and outpatient facilities of the New York University Medical Center/Bellevue Hospital and the Hospital for Joint Diseases. PATIENTS: Case patients were 22 patients hospitalized with disease exacerbation and no evidence of parenchymal lung disease on chest roentgenogram. Four patients with stable disease were followed in the outpatient clinic, and five healthy normal volunteers served as controls. MEASUREMENTS: Plasma levels of complement split products (C3a, factor Bb fragment), alveolar-arterial (A-a) Po2 gradients, and pulmonary function were measured. MAIN RESULTS: Nine episodes of hypoxemia or hypocapnia (mean A-a gradient, 30.4 +/- 4.8 mm Hg) or both (despite normal chest roentgenogram results) were noted in six hospitalized patients (group 1). Gas exchange improved within 72 hours of steroid therapy (mean A-a gradient, 11.6 +/- 4.3 mm Hg; P less than 0.01). These patients had an elevated initial mean C3a level (938.4 +/- 246.8 ng/mL) that decreased within 72 hours (407.8 +/- 80.9 ng/mL; P less than 0.01), concomitant with improved oxygenation. Ventilation-perfusion scans, obtained for four of six group 1 patients, excluded pulmonary emboli. Four hospitalized patients (group 2) had a normal A-a gradient (mean, 7.5 +/- 2.7 mm Hg). The mean C3a level of this group (358.3 +/- 39.2 ng/mL) was lower than that of group 1 (P less than 0.05). Four patients with stable disease (group 3) had a mean A-a gradient and a mean C3a level of 3.3 +/- 2.7 mm Hg and 237.8 +/- 105.7 ng/mL, respectively, similar to values found in five normal volunteers, in whom the mean A-a gradient was 3.7 +/- 1.7 mm Hg and the mean C3a level was 124.8 +/- 9.2 ng/mL. CONCLUSION: A syndrome of reversible hypoxemia, unassociated with parenchymal lung disease, is unexpectedly common in acutely ill, hospitalized patients with systemic lupus erythematosus. The pathogenesis of this syndrome is unclear, although the data are compatible with the hypothesis that hypoxemia may be related to pulmonary leukoaggregation.

Effect of CD14 blockade in rabbits with Escherichia coli pneumonia and sepsis.

CD14, a pattern recognition receptor found on myeloid cells, is a critical component of the innate immune system that mediates local and systemic host responses to Gram-negative and Gram-positive bacterial products. Previous studies in normal animals have tested the effect of CD14 blockade on the systemic response to i.v. LPS. The goals of the study were to determine whether CD14 blockade protected against the deleterious systemic response associated with Escherichia coli pneumonia and to determine whether this strategy affected the pulmonary response to tissue infection. Rabbits were pretreated with either anti-CD14 mAb or isotype control mAb at 2.5 mg/kg. E. coli (1 x 109 CFU) was inoculated into the lungs, and the animals were observed for either 4 or 24 h. The blockade of CD14 improved the mean arterial blood pressure (p = 0.001) and decreased the i.v. fluid requirements (p = 0.01). Although this therapy protected the vascular compartment, rabbits treated with anti-CD14 mAb had increased bacterial burdens in the bronchoalveolar lavage fluid recovered from the instilled lung (p = 0.005) and widened alveolar-arterial oxygen difference. Blockade of CD14 prevents the deleterious systemic responses that occur in sepsis; however, other measures are necessary to control bacterial proliferation at the primary site of infection.

Alveolar and airway sites of nitric oxide inflammation in treated asthma.

The goal of this study was to identify airway and alveolar site(s) of inflammation using exhaled nitric oxide (NO) as a marker in treated patients with asthma, including response to oral corticosteroids, and correlate these sites with expiratory airflow limitation. In 53 (24 male) patients with asthma, age 43 +/- 23 years (mean +/- SD) and all on inhaled corticosteroids, post 180 microg aerosolized albuterol, FEV(1) was 74 +/- 23% predicted and FEV(1)/FVC was 68 +/- 11%. Exhaled NO at 100 ml/second was 27 +/- 23 ppb (p < 0.001 compared with normal, 12 +/- 15 ppb). Bronchial NO maximal flux was 2.4 +/- 3.1 nl/second (p < 0.001 compared with normal, 0.85 +/- 0.55). Alveolar NO concentration was 7.0 +/- 7.4 ppb (p = 0.01 compared with the normal value, 3.2 +/- 2.0 ppb). There was no significant correlation between FEV(1) % predicted or lung elastic recoil and NO bronchial flux or alveolar concentration. However, there was a weak but significant correlation between NO bronchial flux and alveolar concentration (Spearman r = 0.50, p < 0.001). In 10 subjects with asthma on inhaled corticosteroids, 5 days of 30 mg prednisone resulted in isolated significant decreases in NO alveolar concentration, from 13 +/- 10 to 4 +/- 4 ppb (p = 0.002). Despite treatment, including inhaled corticosteroids, patients with asthma may have ongoing separate airway and alveolar sites of NO inflammation, the latter responsive to oral corticosteroids.