Proposal of selective wedge instillation of pulmonary surfactant for COVID-19 pneumonia based on computational fluid dynamics simulation.

BACKGROUND: The most important target cell of SARS-CoV-2 is Type II pneumocyte which produces and secretes pulmonary surfactant (PS) that prevents alveolar collapse. PS instillation therapy is dramatically effective for infant respiratory distress syndrome but has been clinically ineffective for ARDS. Nowadays, ARDS is regarded as non-cardiogenic pulmonary edema with vascular hyper-permeability regardless of direct relation to PS dysfunction. However, there is a possibility that this ineffectiveness of PS instillation for ARDS is caused by insufficient delivery. Then, we performed PS instillation simulation with realistic human airway models by the use of computational fluid dynamics, and investigated how instilled PS would move in the liquid layer covering the airway wall and reach to alveolar regions. METHODS: Two types of 3D human airway models were prepared: one was from the trachea to the lobular bronchi and the other was from a subsegmental bronchus to respiratory bronchioles. The thickness of the liquid layer covering the airway was assigned as 14 % of the inner radius of the airway segment. The liquid layer was assumed to be replaced by an instilled PS. The flow rate of the instilled PS was assigned a constant value, which was determined by the total amount and instillation time in clinical use. The PS concentration of the liquid layer during instillation was computed by solving the advective-diffusion equation. RESULTS: The driving pressure from the trachea to respiratory bronchioles was calculated at 317 cmH2O, which is about 20 times of a standard value in conventional PS instillation method where the driving pressure was given by difference between inspiratory and end-expiratory pressures of a ventilator. It means that almost all PS does not reach the alveolar regions but moves to and fro within the airway according to the change in ventilator pressure. The driving pressure from subsegmental bronchus was calculated at 273 cm H2O, that is clinically possible by wedge instillation under bronchoscopic observation. CONCLUSIONS: The simulation study has revealed that selective wedge instillation under bronchoscopic observation should be tried for COVID-19 pneumonia before the onset of ARDS. It will be also useful for preventing secondary lung fibrosis.

Elastic power but not driving power is the key promoter of ventilator-induced lung injury in experimental acute respiratory distress syndrome.

BACKGROUND: We dissected total power into its primary components to resolve its relative contributions to tissue damage (VILI). We hypothesized that driving power or elastic (dynamic) power offers more precise VILI risk indicators than raw total power. The relative correlations of these three measures of power with VILI-induced histologic changes and injury biomarkers were determined using a rodent model of acute respiratory distress syndrome (ARDS). Herein, we have significantly extended the scope of our previous research. METHODS: Data analyses were performed in male Wistar rats that received endotoxin intratracheally to induce ARDS. After 24 h, they were randomized to 1 h of volume-controlled ventilation with low VT = 6 ml/kg and different PEEP levels (3, 5.5, 7.5, 9.5, and 11 cmH2O). Applied levels of driving power, dynamic power inclusive of PEEP, and total power were correlated with VILI indicators [lung histology and biological markers associated with inflammation (interleukin-6), alveolar stretch (amphiregulin), and epithelial (club cell protein (CC)-16) and endothelial (intercellular adhesion molecule-1) cell damage in lung tissue]. RESULTS: Driving power was higher at PEEP-11 than other PEEP levels. Dynamic power and total power increased progressively from PEEP-5.5 and PEEP-7.5, respectively, to PEEP-11. Driving power, dynamic power, and total power each correlated with the majority of VILI indicators. However, when correlations were performed from PEEP-3 to PEEP-9.5, no relationships were observed between driving power and VILI indicators, whereas dynamic power and total power remained well correlated with CC-16 expression, alveolar collapse, and lung hyperinflation. CONCLUSIONS: In this mild-moderate ARDS model, dynamic power, not driving power alone, emerged as the key promoter of VILI. Moreover, hazards from driving power were conditioned by the requirement to pass a tidal stress threshold. When estimating VILI hazard from repeated mechanical strains, PEEP must not be disregarded as a major target for modification.

Tissue remodelling in pulmonary fibrosis.

Many lung diseases result in fibrotic remodelling. Fibrotic lung disorders can be divided into diseases with known and unknown aetiology. Among those with unknown aetiology, idiopathic pulmonary fibrosis (IPF) is a common diagnosis. Because of its progressive character leading to a rapid decline in lung function, it is a fatal disease with poor prognosis and limited therapeutic options. Thus, IPF has motivated many studies in the last few decades in order to increase our mechanistic understanding of the pathogenesis of the disease. The current concept suggests an ongoing injury of the alveolar epithelium, an impaired regeneration capacity, alveolar collapse and, finally, a fibroproliferative response. The origin of lung injury remains elusive but a diversity of factors, which will be discussed in this article, has been shown to be associated with IPF. Alveolar epithelial type II (AE2) cells play a key role in lung fibrosis and their crucial role for epithelial regeneration, stabilisation of alveoli and interaction with fibroblasts, all known to be responsible for collagen deposition, will be illustrated. Whereas mechanisms of collagen deposition and fibroproliferation are the focus of many studies in the field, the awareness of other mechanisms in this disease is currently limited to biochemical and imaging studies including quantitative assessments of lung structure in IPF and animal models assigning alveolar collapse and collapse induration crucial roles for the degradation of the lung resulting in de-aeration and loss of surface area. Dysfunctional AE2 cells, instable alveoli and mechanical stress trigger remodelling that consists of collapsed alveoli absorbed by fibrotic tissue (i.e., collapse induration).

Respiratory function and mechanics in pinnipeds and cetaceans.

In this Review, we focus on the functional properties of the respiratory system of pinnipeds and cetaceans, and briefly summarize the underlying anatomy; in doing so, we provide an overview of what is currently known about their respiratory physiology and mechanics. While exposure to high pressure is a common challenge among breath-hold divers, there is a large variation in respiratory anatomy, function and capacity between species - how are these traits adapted to allow the animals to withstand the physiological challenges faced during dives? The ultra-deep diving feats of some marine mammals defy our current understanding of respiratory physiology and lung mechanics. These animals cope daily with lung compression, alveolar collapse, transient hyperoxia and extreme hypoxia. By improving our understanding of respiratory physiology under these conditions, we will be better able to define the physiological constraints imposed on these animals, and how these limitations may affect the survival of marine mammals in a changing environment. Many of the respiratory traits to survive exposure to an extreme environment may inspire novel treatments for a variety of respiratory problems in humans.

Prognostic significance of alveolar collapse in lung invasive adenocarcinoma and its relationship with tumor infiltrating lymphocytes.

This study aims to investigate the correlations between alveolar collapse, tumor size, and tumor infiltrating lymphocytes (TILs), while also evaluating the prognostic significance of alveolar collapse in invasive lung adenocarcinoma. 355 patients with solitary invasive lung adenocarcinoma were divided into two groups based on the maximum diameter of alveolar collapse: alveolar collapse ≤ 5 mm group and alveolar collapse > 5 mm group. Differences in clinicopathological characteristics, tumor size, TILs, and prognosis were compared between the two groups. The alveolar collapse > 5 mm group had a higher mean age, larger tumor diameter, and increased TILs levels compared to the alveolar collapse ≤ 5 mm group (P < 0.05). A moderate positive correlation was observed between alveolar collapse and tumor size (r = 0.646, P < 0.001). Lung adenocarcinoma with alveolar collapse > 5 mm demonstrated superior 5-year survival and acted as an independent prognostic indicator (HR=0.152, P = 0.004) in multivariate Cox regression analysis, alongside tumor size (HR=10.172, P = 0.034) and lymph node metastasis (HR=2.88, P = 0.017). The size of alveolar collapse is associated with TILs abundance, suggesting that the immune microenvironment may play a crucial role in alveolar collapse formation. Pathologists should take note of alveolar collapse in lung adenocarcinoma.

Ex-vivo 1.5T MR Imaging versus CT in Estimating the Size of the Pathologically Invasive Component of Lung Adenocarcinoma Spectrum Lesions.

PURPOSE: The purpose of this study was to investigate whether ex-vivo MRI enables accurate estimation of the invasive component of lung adenocarcinoma. METHODS: We retrospectively reviewed 32 patients with lung adenocarcinoma who underwent lung lobectomy. The specimens underwent MRI at 1.5T. The boundary between the lesion and the normal lung was evaluated on a 5-point scale in each three MRI sequences, and a one-way analysis of variance and post-hoc tests were performed. The invasive component size was measured histopathologically. The maximum diameter of each solid component measured on CT and MR T1-weighted (T1W) images and the maximum size obtained from histopathologic images were compared using the Wilcoxon signed-rank test. Inter-reader agreement was evaluated using intraclass correlation coefficients (ICC). RESULTS: T1W images were determined to be optimal for the delineation of the lesions (P < 0.001). The histopathologic invasive area corresponded to the area where the T1W ex-vivo MR image showed a high signal intensity that was almost equal to the intravascular blood signal. The maximum diameter of the solid component on CT was overestimated compared with the maximum invasive size on histopathology (mean, 153%; P < 0.05), while that on MRI was evaluated mostly accurately without overestimation (mean, 108%; P = 0.48). The interobserver reliability of the measurements using CT and MRI was good (ICC = 0.71 on CT, 0.74 on MRI). CONCLUSION: Ex-vivo MRI was more accurate than conventional CT in delineating the invasive component of lung adenocarcinoma.

Differentiation of adenocarcinoma in situ with alveolar collapse from minimally invasive adenocarcinoma or invasive adenocarcinoma appearing as part-solid ground-glass nodules (≤ 2 cm) using computed tomography.

PURPOSE: To investigate the differentiating computed tomographic (CT) features between adenocarcinoma in situ (AIS) with alveolar collapse and minimally invasive adenocarcinoma (MIA) or invasive adenocarcinoma (IA) appearing as part-solid nodules. METHODS: A total of 147 consecutive patients with 157 pathology-confirmed part-solid ground-glass nodules (GGNs) ≤ 20 mm without other pathological condition such as inflammation and fibrosis who underwent chest CT were included. RESULTS: The 157 part-solid GGNs included 33 (21.02%) pathologically confirmed AISs with alveolar collapse. Multivariate analysis revealed that smaller lesion size (odds ratio [OR] 0.671), and well-defined border (OR 5.544), concentrated distribution (OR 7.994), and homogeneity of the solid portion (OR 4.365) were significant independent predictors for differentiating AIS with alveolar collapse from MIA (P < 0.05) with excellent accuracy (area under receiver operating characteristic [ROC] curve, 0.902). Multivariate analysis revealed that smaller lesion size (OR 0.782), and size (OR 0.821), well-defined border (OR 5.752), and homogeneity of solid portion (OR 6.182) were significant independent predictors differentiating AIS with alveolar collapse from IA (P < 0.05) with excellent accuracy (area under ROC curve 0.910). CONCLUSION: Among part-solid GGNs, AIS with alveolar collapse can be accurately differentiated from MIA on the basis of smaller lesion size, well-defined border, concentrated distribution, and homogeneity of solid portion, and from IA according to smaller lesion size, and smaller size, well-defined border, and homogeneity of solid portion.

Microscopic anatomical, immunohistochemical, and morphometric characterization of the terminal airways of the lung in cetaceans.

The lungs of cetaceans undergo anatomical and physiological adaptations that facilitate extended breath-holding during dives. Here, we present new insights on the ontogeny of the microscopic anatomy of the terminal portion of the airways of the lungs in five cetacean species: the fin whale (Balaenoptera physalus); the sperm whale (Physeter macrocephalus), the Cuvier's beaked whale (Ziphius cavirostris); the bottlenose dolphin (Tursiops truncatus); and the striped dolphin (Stenella coeruleoalba). We (a) studied the histology of the terminal portion of the airways; (b) used immunohistochemistry (IHC) to characterize the muscle fibers with antibodies against smooth muscle (sm-) actin, sm-myosin, and desmin; (c) the innervation of myoelastic sphincters (MESs) with an antibody against neurofilament protein; and (d) defined the diameter of the terminal bronchioles, the diameter and length of the alveoli, the thickness of the septa, the major and minor axis, perimeter and section area of the cartilaginous rings by quantitative morphometric analyses in partially inflated lung tissue. As already reported in the literature, in bottlenose and striped dolphins, a system of MESs was observed in the terminal bronchioles. Immunohistochemistry confirmed the presence of smooth muscle in the terminal bronchioles, alveolar ducts, and alveolar septa in all the examined species. Some neurofilaments were observed close to the MESs in both bottlenose and striped dolphins. In fin, sperm, and Cuvier's beaked whales, we noted a layer of longitudinal smooth muscle going from the terminal bronchioles to the alveolar sacs. The morphometric analysis allowed to quantify the structural differences among cetacean species by ranking them into groups according to the adjusted mean values of the morphometric parameters measured. Our results contribute to the current understanding of the anatomy of the terminal airways of the cetacean lung and the role of the smooth muscle in the alveolar collapse reflex, crucial for prolonged breath-holding diving.

Acute exposure to C60 fullerene damages pulmonary mitochondrial function and mechanics.

C60 fullerene (C60) nanoparticles, a nanomaterial widely used in technology, can offer risks to humans, overcome biological barriers, and deposit onto the lungs. However, data on its putative pulmonary burden are scanty. Recently, the C60 interaction with mitochondria has been described in vitro and in vivo. We hypothesized that C60 impairs lung mechanics and mitochondrial function. Thirty-five male BALB/c mice were randomly divided into two groups intratracheally instilled with vehicle (0.9% NaCl + 1% Tween 80, CTRL) or C60 (1.0 mg/kg, FUL). Twenty-four hours after exposure, 15 FUL and 8 CTRL mice were anesthetized, paralyzed, and mechanically ventilated for the determination of lung mechanics. After euthanasia, the lungs were removed en bloc at end-expiration for histological processing. Lung tissue elastance and viscance were augmented in FUL group. Increased inflammatory cell number, alveolar collapse, septal thickening, and pulmonary edema were detected. In other six FUL and six CTRL mice, mitochondria expressed reduction in state 1 respiration [FUL = 3.0 ± 1.14 vs. CTRL = 4.46 ± 0.9 (SEM) nmol O2/min/mg protein, p = 0.0210], ATP production (FUL = 122.6 ± 18 vs. CTRL = 154.5 ± 14 µmol/100 µg protein, p = 0.0340), and higher oxygen consumption in state 4 [FUL = 12.56 ± 0.9 vs. CTRL = 8.26 ± 0.6], generation of reactive oxygen species (FUL 733.1 ± 169.32 vs. CTRL = 486.39 ± 73.1 nmol/100 µg protein, p = 0.0313) and reason ROS/ATP [FUL = 8.73 ± 2.3 vs. CTRL = 2.99 ± 0.3]. In conclusion, exposure to fullerene C60 impaired pulmonary mechanics and mitochondrial function, increased ROS concentration, and decrease ATP production.

Revisiting atelectasis in lung units with low ventilation/perfusion ratios.

Patients on high inspired O2 concentrations are at risk of atelectasis, a problem that has been quantitatively assessed using analysis of ratio of ventilation to perfusion (V̇a/Q̇) equations. This approach ignores the potential of the elastic properties of the lung to support gas exchange through "apneic" oxygenation in units with no tidal ventilation, and is based on an error in the conservation of mass equations. To fill this gap, we correct the error and compare the pressure drops associated with apneic gas exchange with the pressure differences that can be supported by lung recoil. We analyze a worst case scenario: a small test unit in the Weibel model A tree structure with zero tidal ventilation, 100% inspired O2, the rest of the lung being normally ventilated tidally. We first computed the gas flux to the (unventilated) test unit and estimated the associated pressure drops. We then computed the difference in local gas pressure relative to the surrounding lung that would cause the unit to collapse. We compared these two, and finally computed the degree of airway narrowing that would effect change from the stable (apneic gas exchange) regime to the unstable regime leading to collapse. We find that except under extreme conditions of loss of airway caliber exceeding roughly 90%, lung recoil is sufficient to maintain oxygenation through convective transport alone. We further argue that the fundamental V̇a/Q̇ equations are invalid in these circumstances, and that the issue of atelectasis in low V̇a/Q̇ will require modifications to account for this additional mode of gas exchange. NEW & NOTEWORTHY Breathing high concentrations of oxygen increases the likelihood of atelectasis because of oxygen absorption, which is thought to be inevitable in regions with relatively low ventilation/perfusion ratios. However, airspaces of the lung resist collapse because of the forces of interdependence, and can, with low or even zero active tidal ventilation, draw in an inspiratory flow of oxygen sufficient to replace the oxygen consumed, thus preventing collapse of airspaces served by all but the most narrowed airways.

Regional pulmonary effects of bronchoalveolar lavage procedure determined by electrical impedance tomography.

BACKGROUND: The provision of guidance in ventilator therapy by continuous monitoring of regional lung ventilation, aeration and respiratory system mechanics is the main clinical benefit of electrical impedance tomography (EIT). A new application was recently described in critically ill patients undergoing diagnostic bronchoalveolar lavage (BAL) with the intention of using EIT to identify the region where sampling was performed. Increased electrical bioimpedance was reported after fluid instillation. To verify the accuracy of these findings, contradicting the current EIT knowledge, we have systematically analysed chest EIT data acquired under controlled experimental conditions in animals undergoing a large number of BAL procedures. METHODS: One hundred thirteen BAL procedures were performed in 13 newborn piglets positioned both supine and prone. EIT data was obtained at 13 images before, during and after each BAL. The data was analysed at three time points: (1) after disconnection from the ventilator before the fluid instillation and by the ends of fluid (2) instillation and (3) recovery by suction and compared with the baseline measurements before the procedure. Functional EIT images were generated, and changes in pixel electrical bioimpedance were calculated relative to baseline. The data was examined in the whole image and in three (ventral, middle, dorsal) regions-of-interest per lung. RESULTS: Compared with the baseline phase, chest electrical bioimpedance fell after the disconnection from the ventilator in all animals in both postures during all procedures. The fluid instillation further decreased electrical bioimpedance. During fluid recovery, electrical bioimpedance increased, but not to baseline values. All effects were highly significant (p < 0.001). The fractional changes in individual regions-of-interest were posture-dependent. The regional fall in electrical bioimpedance was smaller in the ventral and larger in the dorsal regions after the fluid instillation than after the initial disconnection to ambient pressure in supine animals (p < 0.001) whereas these changes were of comparable amplitude in prone position. CONCLUSIONS: The results of this study show a regionally dissimilar initial fall in electrical bioimpedance caused by non-uniform aeration loss at the beginning of the BAL procedure. They also confirm a further pronounced fall in bioimpedance during fluid instillation, incomplete recovery after suction and a posture-dependent distribution pattern of these effects.

Bloody Bronchial Cast Formation Due to Alveolar Hemorrhage Associated with H1N1 Influenza Infection.

A previously healthy 55-year-old man with H1N1 influenza A presented with severe respiratory failure and cardiac arrest. Following the return of spontaneous circulation, venovenous extracorporeal membrane oxygenation was required to maintain oxygenation. On day 2, bronchoscopy revealed a bloody bronchial cast obstructing the right main bronchus. A pathological examination revealed that it was composed of intrabronchial and intra-alveolar hemorrhagic tissue. Unfortunately, the patient died due to severe brain ischemia; a subsequent autopsy revealed marked alveolar hemorrhage. It is possible that anticoagulant therapy, alveolar collapse, and neuromuscular blocking agents provoked cast development in this case.

The role of high airway pressure and dynamic strain on ventilator-induced lung injury in a heterogeneous acute lung injury model.

BACKGROUND: Acute respiratory distress syndrome causes a heterogeneous lung injury with normal and acutely injured lung tissue in the same lung. Improperly adjusted mechanical ventilation can exacerbate ARDS causing a secondary ventilator-induced lung injury (VILI). We hypothesized that a peak airway pressure of 40 cmH2O (static strain) alone would not cause additional injury in either the normal or acutely injured lung tissue unless combined with high tidal volume (dynamic strain). METHODS: Pigs were anesthetized, and heterogeneous acute lung injury (ALI) was created by Tween instillation via a bronchoscope to both diaphragmatic lung lobes. Tissue in all other lobes was normal. Airway pressure release ventilation was used to precisely regulate time and pressure at both inspiration and expiration. Animals were separated into two groups: (1) over-distension + high dynamic strain (OD + HDS, n = 6) and (2) over-distension + low dynamic strain (OD + LDS, n = 6). OD was caused by setting the inspiratory pressure at 40 cmH2O and dynamic strain was modified by changing the expiratory duration, which varied the tidal volume. Animals were ventilated for 6 h recording hemodynamics, lung function, and inflammatory mediators followed by an extensive necropsy. RESULTS: In normal tissue (NT), OD + LDS caused minimal histologic damage and a significant reduction in BALF total protein (p < 0.05) and MMP-9 activity (p < 0.05), as compared with OD + HDS. In acutely injured tissue (ALIT), OD + LDS resulted in reduced histologic injury and pulmonary edema (p < 0.05), as compared with OD + HDS. CONCLUSIONS: Both NT and ALIT are resistant to VILI caused by OD alone, but when combined with a HDS, significant tissue injury develops.

Effects of acute hypercapnia with and without acidosis on lung inflammation and apoptosis in experimental acute lung injury.

We investigated the effects of acute hypercapnic acidosis and buffered hypercapnia on lung inflammation and apoptosis in experimental acute lung injury (ALI). Twenty-four hours after paraquat injection, 28 Wistar rats were randomized into four groups (n=7/group): (1) normocapnia (NC, PaCO2=35-45 mmHg), ventilated with 0.03%CO2+21%O2+balancedN2; (2) hypercapnic acidosis (HC, PaCO2=60-70 mmHg), ventilated with 5%CO2+21%O2+balancedN2; and (3) buffered hypercapnic acidosis (BHC), ventilated with 5%CO2+21%O2+balancedN2 and treated with sodium bicarbonate (8.4%). The remaining seven animals were not mechanically ventilated (NV). The mRNA expression of interleukin (IL)-6 (p=0.003), IL-1ß (p<0.001), and type III procollagen (PCIII) (p=0.001) in lung tissue was more reduced in the HC group in comparison with NC, with no significant differences between HC and BHC. Lung and kidney cell apoptosis was reduced in HC and BHC in comparison with NC and NV. In conclusion, in this experimental ALI model, hypercapnia, regardless of acidosis, reduced lung inflammation and lung and kidney cell apoptosis.

Permanent alveolar collapse is the predominant mechanism in idiopathic pulmonary fibrosis.

Alveolar epithelial cell loss and impaired epithelial cell regeneration are currently accepted as central initiating events in idiopathic pulmonary fibrosis (IPF), but subsequent downstream effects remain uncertain. The most accepted downstream effect is aberrant and dysregulated mesenchymal cell proliferation and excess extracellular matrix (ECM) accumulation. However, biochemical and imaging studies have perhaps somewhat surprisingly indicated little increase in total lung collagen and lung tissue, and have rather shown a substantial decrease in lung aeration and lung air volume. Loss of tissue aeration is a consequence of alveolar collapse, which occurs in IPF as a result of apposition and septal incorporation of denuded basal lamina. Permanent alveolar collapse is well-documented following epithelial injury, has the ability to mimic interstitial fibrosis radiologically and histologically, and is a better supported explanation than dysregulated fibroblast proliferation and excess ECM accumulation for the constellation of findings in patients with IPF.

The clinical value of lung recruitment maneuver in preventing alveolar collapse after bronchoscopy / 中华胸心血管外科杂志

Objective To investigate the effect of lung recruitment maneuver on alveolar collapse after fiber support bronchoscopy,and to evaluate its clinical value.Methods Since April 2014 and April 2017 in underwent deep hypothermia and stop of 60 cases of hypoxemia in patients with postoperative aortic circulation as the research object,according to the random number distribution method.The average score of the two groups,each group with 30 cases in each.The control group was treated with conventional fiber bronchoscopy and end expiratory positive pressure ventilation in the treatment,observation group patients on the basis of the application of lung recruitment method to carry on the treatment.Observation compared two groups of patients with lung recruitment maneuver and respiration and circulation of the parameter variations and mechanical ventilation in time.Results Two groups of patients with treatment of the parameters,the difference was not statistically significant (P ＞0.05);after treatment,observation group of patients with oxygen synthetic index and mechanical ventilation time and the control group was significant difference compared with statistical significance(P ＜ 0.05);and two groups of patients with arterial carbon dioxide into change of pressure and tidal volume before and after the treatment were not significant,no statistical significance(P ＞ 0.05).Two groups of patients with the circulatory system index tends to be stable,no significant change (P ＞0.05).Conclusion The use of bronchoscopy in patients with aortic dissection after the examination of hypoxia,application of lung recruitment maneuver method for treatment,can improve the patient's oxygenation index,reduce the time of mechanical ventilation in patients with.