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The health impact of environmental pollution involving an increase in human diseases has been subject to extensive study in recent decades. The methodology in biomimetic investigation of these pathophysiologic events is still in progress to uncover the gaps in knowledge associated with pollution and its influences on health. Herein, we describe a comprehensive evaluation of environmental pollutant-caused lung inflammation and injury using a microfluidic pulmonary alveolus platform with alveolar-capillary interfaces. We performed a microfluidic three-dimensional coculture with physiological microenvironment simulation at microscale control and demonstrated a reliable reconstruction of tissue layers including alveolar epithelium and microvascular endothelium with typical mechanical, structural, and junctional integrity, as well as viability. On-chip detection and analysis of pulmonary alveolus responses focusing on various inflammatory and injurious dynamics to the respective pollutant stimulations were achieved in the coculture-based microfluidic pulmonary alveolus model, in comparison with common on-chip monoculture and off-chip culture tools. We confirmed the synergistic effects of the epithelial and endothelial interfaces on the stimuli resistance and verified the importance of creating complex tissue microenvironments in vitro to explore pollution-involved human pathology. We believe the microfluidic approach presents great promise in environmental monitoring, drug discovery, and tissue engineering.

The deposition and transport of toxicants on pulmonary surfactant are important processes in human health and medical care. We have introduced classical density functional theory (CDFT) to provide insight into this process. Nine typical toxicants in PM2.5 were considered, and their free energy and structural information have been examined. The free energy profile indicates that PbO, As2O3, and CdO are the three toxicants most easily deposited in the pulmonary alveolus, which is consistent with survey data. CuO appears to be the easiest toxicant to transport through the surfactant. Structural analysis indicates that the toxicants tend to pass through the surfactant with rotation. The configuration of the pulmonary surfactant was examined by extending our previous work to polymer systems, and it appears that both the configurational entropy and the direct interaction between the surfactant and the toxicant dominate the configuration of the pulmonary surfactant.

COVID-19 is a disease caused by the SARS-CoV virus. It stands for severe acute respiratory syndrome, which affects the lungs. The process of replication and progression of the COVID-19 virus causes the formation of an excessive amount of reactive oxygen species and inflammation. Many studies have been carried out that have demonstrated that hydrogen has strong anti-inflammatory properties. It reduces hypotension and other symptoms by reducing inflammation and oxidative stress. Oxygen mixture, enriched with Hydrogen, - helps to reduce the resistance of the respiratory tract and frees up access to the pulmonary alveolus, which improves the penetration of oxygen into the lungs. Since hydrogen is an antioxidant, it helps to reduce the burden on the immune system, helps to maintain the body's health and its ability to quickly recover. When electrolysers are used to produce an oxygen-hydrogen mixture, alkaline mist and other impurities can enter the patient's lungs and cause poisoning and chemical burns. For this reason, the use of atomic hydrogen obtained from metal hydride sources for ventilation of the lungs will be more effective for treating COVID-19 than a molecular hydrogen-oxygen mixture from an electrolyzer. A functional diagram of a metal hydride source of atomic hydrogen to an artificial lung ventilator is shown. It is possible to create a series of hydrogen storage tanks of various capacities.

The purpose of this study was to explore the damage effects and injury mechanism of free-field explosion shock waves on rabbit lungs. Six free-field explosion experiments, each with 500 g trinitrotoluene (TNT), were conducted as the shock wave overpressure acting on the rabbits was measured. The peak overpressure of the shock wave was 533, 390, 249, 102, and 69 kPa at the respective test points. Damage to the rabbit lungs caused by shock wave overpressure was investigated through observation, anatomical analysis, and hematoxylin-eosin (HE) staining processing. The shock wave overpressure of 69–102 kPa caused mild-to-moderate injury; the shock wave overpressure of 102–249 kPa caused moderate injury; the shock wave overpressure of 249–390 kPa resulted in moderate-to-severe injury; and the shock wave overpressure of 390–533 kPa caused severe injury to the rabbit. Mild, moderate, and severe injuries destroyed some, most, or all alveolar structures, correspondingly, as well as producing partial cell apoptosis. The overpressure damage mechanism primarily involves the collapse and rupture of pulmonary alveolus in the lung tissue. As a novel attempt, the investigation provided here may serve to improve the current shock wave injury mechanism.

Diffuse alveolar damage (DAD) is a characteristic histopathologic pattern in most cases of acute respiratory distress syndrome and severe viral pneumonia, such as COVID-19. DAD is characterized by an acute phase with edema, hyaline membranes, and inflammation followed by an organizing phase with pulmonary fibrosis and hyperplasia. The degree of pulmonary fibrosis and surface tension is different in the pathological stages of DAD. The effects of pulmonary fibrosis and surface tension on alveolar sac mechanics in DAD are investigated by using the fluid–structure interaction (FSI) method. The human pulmonary alveolus is idealized by a three-dimensional honeycomb-like geometry, with alveolar geometries approximated as closely packed 14-sided polygons. A dynamic compression-relaxation model for surface tension effects is adopted. Compared to a healthy model, DAD models are created by increasing the tissue thickness and decreasing the concentration of the surfactant. The FSI results show that pulmonary fibrosis is more influential than the surface tension on flow rate, volume, P–V loop, and resistance. The lungs of the disease models become stiffer than those of the healthy models. According to the P–V loop results, the surface tension plays a more important role in hysteresis than the material nonlinearity of the lung tissue. Our study demonstrates the differences in air flow and lung function on the alveolar sacs between the healthy and DAD models.

We aimed to compare the efficacy of the VIO soft coagulation system (VSCS) for the treatment of air leaks by sealing with fibrin glue, and also assess the histological alterations that occur after soft coagulation. A mouse pulmonary air leak model was designed. The pulmonary fistula was subsequently coagulated with the VSCS or sealed with fibrin glue with polyglycolic acid (PGA) sheets. The burst pressure at air leak recurrence was measured in each group, and the results were compared. We also evaluated the histological alterations in the mouse pulmonary air leak model after soft coagulation with the VSCS. The burst pressure in the soft coagulation group (80 W/Effect 5) (median 42.8; range 35.4–53.8 cmH2O) was similar to that in the fibrin glue group (median 41.5; range 34.6–43.9 cmH2O) (p = 0.21). Histological examinations revealed that the visceral pleura remained torn, the structure of the pulmonary alveolus was maintained, and the coagulated fistula was covered with a fibrin membrane in the soft coagulation group. The pressure resistance following soft coagulation was equivalent to that after sealing using fibrin glue with PGA sheets. The air leaks were likely controlled by covering the fistula with a fibrin membrane after soft coagulation with the VSCS.

Background: Pulmonary sclerosing pneumocytoma (PSP) is a rare benign pulmonary tumor that derives from primitive respiratory epithelium of the pulmonary alveolus. The etiology and pathogenesis are still unclear. Histopathological diagnosis focuses on cells that are positive for TTF1, EMA, cytokeratin-7, and CAM 5.2. The aim of our study is to highlight the elevated expression of ALDH and the presence of SOX-2 in pulmonary sclerosing pneumocytoma. Methods: We report five cases of pulmonary sclerosing pneumocytoma undergone surgery at our Division of Thoracic Surgery, during a period between 1994 and 2011. ALDH and SOX-2 markers were also tested for positivity in all the patients. Results: Patients showed elevated expression of ALDH during immunohistochemistry and mild expression of SOX-2, although in two cases in which SOX-2 was highly expressed. Among these two patients, one presented with lymph node recurrence while the other had no recurrence with a PET-positive nodule. In particular, the patient who had developed recurrence had an ALDH score of 4 and a SOX-2 score of 3, whereas the patient with the PET-positive nodule showed an ALDH score of 4 with a mild SOX-2 expression of score 1. Conclusions: This is the first attempt demonstrating the elevated expression of ALDH in this disease. SOX-2 expression was noted in both the patient who developed recurrence and the patient with a PET-positive nodule. We believe that further investigation may be highly useful to better characterize these two markers as well as understand their function.

Pulmonary nodular lymphoid hyperplasia (PNLH) involves proliferative lymphatic tissues and is reportedly associated with inflammatory disease or autoimmune disorders. Herein, we describe a case of PNLH with difficult diagnosis because of antibiotics therapy‐induced reduction in the abnormal tumour shadow. An 86‐year‐old man was admitted for persistent cough and bloody sputum. Computed tomography (CT) revealed a mass in the right middle lobe, which got smaller on treatment with tosufloxacin for pneumonia. Unexpectedly, the tumour shadow remained one month later. Positron emission tomography depicted fluorodeoxyglucose uptake at the site. Although lung cancer was suspected, the mass was non‐diagnostic on transbronchial and CT‐guided biopsies. He was eventually diagnosed with PNLH on post‐surgical histological analysis of the lung mass. Neutrophil accumulation and bacterial lumps were present, indicating Actinomyces infection in the pulmonary alveolus, suggesting that PNLH was associated with pneumonia. Histopathological examination helped identify the aetiology of this rare case of PNLH., A case of pulmonary nodular lymphoid hyperplasia (PNLH) that was difficult to diagnosis because of an abnormal shadow that was reduced due to antibiotics use was described. Histopathological examination indicated a diagnosis of PNLH and the pathological evidence of bacteria suggested an infective aetiology for PNLH.

Mycobacterium tuberculosis (Mtb) is the causative agent for tuberculosis, the most extended infectious disease around the world. When Mtb enters inside the pulmonary alveolus it is rapidly phagocytosed by the alveolar macrophage. Although this controls the majority of inhaled microorganisms, in this case, Mtb survives inside the macrophage and multiplies. A posterior chemokine and cytokine cascade generated by the irruption of monocytes, neutrophils and posteriorly, by T-cells, does not necessarily stop the growth of the granuloma. Interestingly, the encapsulation process built by fibroblasts is able to surround the lesion and stop its growing. The success of this last process determines if the host enters in an asymptomatic latent state or continues into a life-threatening and infective active tuberculosis disease (TB). Understanding such dichotomic process is challenging, and computational modeling can bring new ideas. Thus, we have modeled the different stages of the infection, first in a single alveolus (a sac with a radius of 0.15 millimeters) and, second, inside a secondary lobule (a compartment of the lungs of around 3 cm3). We have employed stochastic reaction-diffusion equations to model the interactions among the cells and the diffusive transport to neighboring alveolus. The whole set of equations have successfully described the encapsulation process and determine that the size of the lesions depends on its position on the secondary lobule. We conclude that size and shape of the secondary lobule are the relevant variables to control the lesions, and, therefore, to avoid the evolution towards TB development. As lesions appear near to interlobular connective tissue they are easily controlled and their growth is drastically stopped, in this sense secondary lobules with a more flattened shape could control better the lesion.

The diffuse alveolar hemorrhage syndrome is characterized by the presence of blood in the pulmonary alveolus from arterioles, venules and pulmonary capillaries, as a consequence of the lesion of the alveolar wall and without an endobronchial alteration. Its presentation includes a classic triad of hemoptysis, anemia and diffuse alveolar infiltrates. It´s a rare but potentially fatal entity and there are no clear data on its real incidence in the pediatric population. We present the case of a previously healthy pediatric patient, immunocompetent, who presented diffuse alveolar hemorrhage syndrome with secondary ventilatory failure. After discarding all possible etiologies, coinfection by Rhinovirus and human Bocavirus was detected through the polymerase chain reaction, determining them as causal factors of the event. Recently, viral infections have been postulated as causing serious lung disease, especially coinfection in immunocompromised patients, in this case Rhinovirus and human Bocavirus; however there are no reports on the syndrome caused by these viruses. DOI: http://dx.doi.org/10.21615/cesmedicina.32.1.6

In this article, we formulate a physiological process through a two-dimensional fluid-structure interaction problem between the airflow and the pulmonary alveolus in the Eulerian-Lagrangian Arbitrary (ALE) frame. This problem arises by coupling the equations of the fluid and the structure, described by the Navier-Stokes equations of evolution for incompressible flows, and an equilibrium equation, respectively.

A major cause of respiratory failure during influenza A virus (IAV) infection is damage to the epithelial–endothelial barrier of the pulmonary alveolus. Damage to this barrier results in flooding of the alveolar lumen with proteinaceous oedema fluid, erythrocytes and inflammatory cells. To date, the exact roles of pulmonary epithelial and endothelial cells in this process remain unclear.Here, we used an in vitro co-culture model to understand how IAV damages the pulmonary epithelial–endothelial barrier. Human epithelial cells were seeded on the upper half of a transwell membrane while human endothelial cells were seeded on the lower half. These cells were then grown in co-culture and IAV was added to the upper chamber.We showed that the addition of IAV (H1N1 and H5N1 subtypes) resulted in significant barrier damage. Interestingly, we found that, while endothelial cells mounted a pro-inflammatory/pro-coagulant response to a viral infection in the adjacent epithelial cells, damage to the alveolar epithelial–endothelial barrier occurred independently of endothelial cells. Rather, barrier damage was associated with disruption of tight junctions amongst epithelial cells, and specifically with loss of tight junction protein claudin-4.Taken together, these data suggest that maintaining epithelial cell integrity is key in reducing pulmonary oedema during IAV infection.

Background and objective The idiopathic interstitial pneumonias (IIPs) are diffuse parenchymal lung disorders that are associated with substantial morbidity and mortality. Early diagnosis and disease stratification of IIP patients are important because these are related with the treatment and prognosis. Idiopathic pulmonary fibrosis (IPF) and nonspecific interstitial pneumonia (NSIP) are two major distinctive pathologic patterns of pulmonary fibrosis. We researched the application of the fluid-structure interaction (FSI) to the respiratory system and compared the pulmonary acinus mechanics and functions in healthy and IIP models. Methods The human pulmonary alveolus is idealized by a three-dimensional honeycomb-like geometry, and a fluid-structure interaction analysis is performed to study the normal and diseased breathing mechanics. The computational domain consists of two generations of alveolar ducts within the pulmonary acinus, with alveolar geometries approximated as closely packed 14-sided polygons. Findings In a normal breathing cycle, the flow rate of the healthy model is significantly larger than that of the NSIP and IPF models. Similar trends are observed for the volume change and the maximum pressure drop. The flow rate and the volume change of the NSIP are almost the same as those of IPF. The maximum pressure drop of NSIP is 5.5% larger than that of IPF. There is a 47% decrease in the pulmonary acinus compliance for the NSIP and IPF compared with that of the healthy model. The acinus resistances of NSIP and IPF are higher than those of the healthy lung by 6.4~11.2%. In particular, the pulmonary acinus resistance of the NSIP lung is higher than that of the IPF lung by 4.5%. Conclusions Our study demonstrates the differences of air flow and lung function in the pulmonary acinus between the healthy and the IIP models. These changes in the lung are important considerations for early diagnosis and disease stratification in patients. Patient-based geometry can to be included in the computational models in future studies.

In this article, we formulate a physiological process through a two-dimensional fluid-structure interaction problem between the airflow and the pulmonary alveolus in the Eulerian-Lagrangian Arbitrary (ALE) frame.This problem arises by coupling the equations of the fluid and the structure, described by the Navier-Stokes equations of evolution for incompressible flows, and an equilibrium equation, respectively. En este artículo, Formulamos un proceso fisiológico, a través de un problema de interacción fluido-estructura bidimensional entre el flujo de aire y el alvéolo pulmonar, en el marco de referencia Euleriano - LagrangianoArbitrario (ALE). Este problema se origina al acoplar las ecuaciones del fluido y de la estructura, descritas por las Ecuaciones de evolución de Navier-Stokes para flujos incompresibles, y una ecuación de equilibrio,respectivamente.

José Hureaux,1,2 Franck Lacœuille,3,4 Frédéric Lagarce,1,5 Marie-Christine Rousselet,6 Aurélien Contini,3,4 Patrick Saulnier,1,7 Jean-Pierre Benoit,1,5 Thierry Urban1,2 1Unité Micro et Nanomédecines Biomimétiques (MINT), Université d’Angers, INSERM 1066, CNRS 6021, Université Bretagne Loire, 2Université d’Angers, CHU, Pôle Hippocrate, Service de Pneumologie, 3Université d’Angers, CHU, Pôle Signal Image Stérilisation, Service de Médecine nucléaire, 4CRCINA, Université Nantes Université Angers, 5Université d’Angers, CHU, Pôle Hippocrate, Pharmacie, 6Université d’Angers, CHU, Pôlede Biologie-Pathologie, Département de Cytologie et d’Histologie Pathologique, 7Université d’Angers, CHU, Service la Recherche Clinique et Innovation, Angers, France Abstract: Lipid nanocapsules (LNCs) are potential drug carriers for pulmonary delivery since they can be nebulized without any structural or functional changes, and the aerosols produced are highly compatible with pulmonary drug delivery in human beings. The alveolar surface tension, in vitro cytotoxicity, biodistribution and pulmonary toxicity in rats of a single endotracheal spray of LNCs or paclitaxel-loaded LNCs were studied. In vitro cytotoxicity of LNCs after a spray remained unchanged. Biodistribution study showed a homogeneous repartition in the lungs in rats with an improvement in lung retention of the radiolabeled tracer loaded in LNCs compared to the absence of LNCs with a lung half-time of 8.8±0.7hours. Bronchoalveolar fluid analysis revealed transient 7-day alveolar inflammation, reaching a maximum between days 2 and 4, characterized by a peak of granulocytes at day 1 followed by a peak of lymphocytes at day 3. Alveolar protein levels were increased at days 3 and 7. Acute inflammation was increased with paclitaxel-loaded LNCs in comparison with blank LNCs but dropped out at day 7. No histological pulmonary lesion was observed at day 60. LNCs lowered surface tension to a greater degree than Curosurf® in a physicochemical model of the pulmonary alveolus. A single pulmonary delivery of LNCs induces a short-term alveolar inflammation with no residual lesions in rats at day 60. These data permit to start the study of LNCs in surfactant replacement therapy. Keywords: lipid nanocapsules, pulmonary drug delivery, biodistribution, toxicity, paclitaxel

Background Chebulic acid (CA) isolated from T. chebula, which has been reported for treating asthma, as a potent anti-oxidant resources. Exposure to ambient urban particulate matter (UPM) considered as a risk for cardiopulmonary vascular dysfunction. To investigate the protective effect of CA against UPM-mediated collapse of the pulmonary alveolar epithelial (PAE) cell (NCI-H441), barrier integrity parameters, and their elements were evaluated in PAE. Methods CA was acquired from the laboratory previous reports. UPM was obtained from the National Institutes of Standards and Technology, and these were collected in St. Louis, MO, over a 24-month period and used as a standard reference. To confirm the protection of PAE barrier integrity, paracellular permeability and the junctional molecules were estimated with determination of transepithelial electrical resistance, Western Blotting, RT-PCR, and fluorescent staining. Results UPM aggravated the generation of reactive oxygen species (ROS) in PAE and also decreased mRNA and protein levels of junction molecules and barrier integrity in NCI-H441. However, CA repressed the ROS in PAE, also improved barrier integrity by protecting the junctional parameters in NCI-H411. Conclusions These data showed that CA resulted in decreased UPM-induced ROS formation, and the protected the integrity of the tight junctions against UPM exposure to PAE barrier. Electronic supplementary material The online version of this article (doi:10.1186/s12906-017-1870-5) contains supplementary material, which is available to authorized users.

In previous studies, we identified 29 tumor-associated antigens (TAAs) and isolated 488 human monoclonal antibodies (mAbs) that specifically bind to one of the 29 TAAs. In the present study, we performed histochemical analysis of 36 freshly resected lung cancer tissues by using 60 mAbs against 27 TAAs. Comparison of the staining patterns of tumor cells, bronchial epithelial cells, and normal pulmonary alveolus cells and interalveolar septum allowed us to determine the type and location of cells that express target molecules, as well as the degree of expression. The patterns were classified into 7 categories. While multiple Abs were used against certain TAAs, the differences observed among them should be derived from differences in the binding activity and/or the epitope. Thus, such data indicate the versatility of respective clones as anti-cancer drugs. Although the information obtained was limited to the lung and bronchial tube, bronchial epithelial cells represent normal growing cells, and therefore, the data are informative. The results indicate that 9 of the 27 TAAs are suitable targets for therapeutic Abs. These 9 Ags include EGFR, HER2, TfR, and integrin α6β4. Based on our findings, a pharmaceutical company has started to develop anti-cancer drugs by using Abs to TfR and integrin α6β4. HGFR, PTP-LAR, CD147, CDCP1, and integrin αvβ3 are also appropriate targets for therapeutic purposes.

Theoretical data for the alveolar amplitude response technique (AART) (J. Appl. Physiol. 41 (1976) 419-424) for assessing lung function was simulated using a single path lung model. This model takes account of stratified inhomogeneities in gas concentrations within the respiratory tree. The data was inserted into previously published parameter recovery techniques that may be used to estimate dead-space volume, alveolar volume and cardiac output. These parameter recovery techniques are based on much simpler mathematical models that do not allow stratified inhomogeneities in gas concentrations. It was found that: (i) recovered dead-space volume depended significantly on the ventilation pattern and on the distribution of volume within of the conducting airways; (ii) alveolar volume was recovered to a good degree of accuracy; and (iii) the recovered value of cardiac output was highly dependent on both the choice of inert gas and parameter recovery technique.

Active sodium transport contributes to liquid clearance from the alveoli. We hypothesized that the magnitude of active transport of alveolar liquid depends on the extent to which the alveolar epithelium is stretched and, consequently, on the degree of alveolar inflation. In a study on 38 adult rabbits, the left lung was filled in vivo with a solution of glucose (10 mmol/l) made isosmotic with plasma, using sodium chloride, and held at a constant airway pressure of 3, 6, or 9 cmH2O for 6 h. Alveolar liquid clearance was measured directly as a flow into a left main bronchial catheter. Control animals were compared with animals in which active epithelial sodium transport was inhibited by adding amiloride and phloridzin (both 1 mmol/l) to the instillate. At low inflation, active sodium transport reversed a secretion of liquid into the alveoli; at high inflation, active sodium transport made little or no contribution to transepithelial flow. Hydraulic conductance of the left lung was 1.57 microliters.min-1.cmH2O-1.kg body wt-1. The experiments suggest that pulmonary inflation renders active liquid clearance ineffective.

Although gastric acid aspiration causes rapid lung inflammation and acute lung injury, the initiating mechanisms are not known. To determine alveolar epithelial responses to acid, we viewed live alveoli of the isolated lung by fluorescence microscopy, then we microinjected the alveoli with HCl at pH of 1.5. The microinjection caused an immediate but transient formation of molecule-scale pores in the apical alveolar membrane, resulting in loss of cytosolic dye. However, the membrane rapidly resealed. There was no cell damage and no further dye loss despite continuous HCl injection. Concomitantly, reactive oxygen species (ROS) increased in the adjacent perialveolar microvascular endothelium in a Ca2+-dependent manner. By contrast, ROS did not increase in wild-type mice in which we gave intra-alveolar injections of polyethylene glycol (PEG)-catalase, in mice overexpressing alveolar catalase, or in mice lacking functional NADPH oxidase (Nox2). Together, our findings indicate the presence of an unusual proinflammatory mechanism in which alveolar contact with acid caused membrane pore formation. The effect, although transient, was nevertheless sufficient to induce Ca2+ entry and Nox2-dependent H2O2 release from the alveolar epithelium. These responses identify alveolar H2O2 release as the signaling mechanism responsible for lung inflammation induced by acid and suggest that intra-alveolar PEG-catalase might be therapeutic in acid-induced lung injury.

A deposition of submicron spherical particles in gravity force field in a model of a single human alveolus was investigated. To mimic the realistic breathing patterns in the lungs, alveolar tissue was designed as a compressible and homogenous material which undergoes the expansion and contraction caused by the change of pressure. The wide range of stiffness values and elasticity of the tissue were taken into account to explore the influence of pathological cases in the process of flow transport in the alveolar part of the human breathing system. A fluid-structure interaction model (FSI) incorporated into Adina software was used to model the fluid flow in the alveolus. The transport and the deposition of the aerosol particles were modeled using Brownian Dynamics algorithm. The obtained results indicate a strong influence of the mechanical properties of the tissue on the fluid flow and the deposition of aerosol particles.

The pulmonary alveolus, terminal gas-exchange unit of the lung, is composed of alveolar epithelial and endothelial cells separated by a thin basement membrane and interstitial space. These cells participate in the maintenance of a delicate system regulated not only by biological factors but also by the mechanical environment of the lung, which undergoes dynamic deformation during breathing. Clinical and animal studies as well as cell culture studies point toward a strong influence of mechanical forces on lung cells and tissues including effects on growth and repair, surfactant release, injury, and inflammation. However, despite substantial advances in our understanding of lung mechanics over the last half century, there are still many unanswered questions regarding the micromechanics of the alveolus and how it deforms during lung inflation. Therefore, the aims of this review are to draw a multidisciplinary account of the mechanics of the alveolus on the basis of its structure, biology, and chemistry and to compare estimates of alveolar deformation from previous studies.

Surfactant dysfunction plays a major role in respiratory distress syndrome (RDS). This research seeks to determine whether the use of natural surfactant, Curosurf™ (Cheisi Farmaceutici, Parma, Italy), accompanied with pressure oscillations at the level of the alveoli can reduce the surface tension in the lung, thereby making it easier for infants with RDS to maintain the required level of functional residual capacity (FRC) without collapse. To simulate the alveolar environment, dynamic surface tension measurements were performed on a modified pulsating bubble surfactometer (PBS) type device and showed that introducing superimposed oscillations about the tidal volume excursion between 10 and 70 Hz in a surfactant bubble lowers interfacial surface tension below values observed using tidal volume excursion alone. The specific mechanisms responsible for this improvement are yet to be established; however it is believed that one mechanism may be the rapid transient changes in the interfacial area increase the number of interfacial binding sites for surfactant molecules, increasing adsorption and diffusion to the interface, thereby decreasing interfacial surface tension. Existing mathematical models in the literature reproduce trends noticed in experiments in the range of breathing frequencies only. Thus, a modification is introduced to an existing model to both incorporate superimposed pressure oscillations and demonstrate that these may improve the dynamic surface tension in the alveoli.

Bronchopulmonary dysplasia (BPD) is characterized by arrested alveolar development and complicated by pulmonary hypertension (PH). NO promotes alveolar growth. Inhaled NO (iNO) ameliorates the BPD phenotype in experimental models and in some premature infants. Arginosuccinate synthetase (ASS) and arginosuccinate lyase (ASL) convert L-citrulline to L-arginine; L-citrulline is regenerated during NO synthesis from L-arginine. Plasma levels of these NO precursors are low in PH. We hypothesized that L-citrulline prevents experimental O2-induced BPD in newborn rats. Rat pups were assigned from birth through postnatal day (P) 14 to room air (RA), RA + L-citrulline, 95% hyperoxia (BPD model), and 95%O2 + L-citrulline. Rat pups exposed to hyperoxia had fewer and enlarged air spaces and decreased capillary density, mimicking human BPD. This was associated with decreased plasma L-arginine and L-citrulline concentrations on P7. L-citrulline treatment significantly increased plasma L-arginine and L-citrulline concentrations and increased ASL protein expression in hyperoxia. L-citrulline preserved alveolar and vascular growth in O2-exposed pups and decreased pulmonary arterial medial wall thickness (MWT) and right ventricular hypertrophy (RVH). Increased lung arginase (ARG) activity in O2-exposed pups was reversed by L-citrulline treatment. L-citrulline supplementation prevents hyperoxia-induced lung injury and PH in newborn rats. L-citrulline may represent a novel therapeutic alternative to iNO for prevention of BPD.

In the lung, epidermal fatty acid-binding protein (E-FABP) is expressed by alveolar macrophages (AM) and alveolar epithelial cells type II (AEII). E-FABP may regulate macrophage activation and is involved in the metabolism of surfactant phospholipids. As macrophage activation and surfactant dysfunction are associated with rejection, we hypothesize that E-FABP expression is changed during acute rejection of pulmonary grafts. Orthotopic left lung transplantations were performed in the Dark Agouti to Lewis and in the isogeneic Lewis to Lewis rat strain combinations. E-FABP expression was analyzed in the lung by immunohistochemistry, immunoblotting and quantitative reverse transcription-polymerase chain reaction (RT-PCR). Alveolar leukocytes obtained by bronchoalveolar lavage were analyzed by RT-PCR. Immunohistochemistry of isografts revealed strong E-FABP immunoreactivity in AEII and a moderate immunoreactivity in AM. In allografts undergoing acute rejection, AM exhibiting increased E-FABP immunoreactivity accumulated. Immunoblots revealed a single band at 15 kDa, which corresponds to the expected molecular mass of E-FABP. The levels of E-FABP mRNA were higher in allografts than in isografts and control lungs. Furthermore, alveolar leukocytes isolated by bronchoalveolar lavage from allografts displayed higher E-FABP mRNA expression levels than leukocytes from isografts and controls. In conclusion, we demonstrate for the first time upregulation of E-FABP expression in AM during severe inflammation.

Allogeneic bone marrow transplantation is a common method used to study the contribution of myeloid and lymphoid cell populations in murine models of disease. The method requires lethal doses of radiation to ablate the bone marrow. Unintended consequences of radiation include organ injury and inflammatory cell activation. The goal of our study was to determine the degree to which bone marrow transplantation alters lungs and to develop a system to protect the lungs during radiation. C57BL/6 mice were subjected to total body irradiation with 900 cGy and then transplanted with bone marrow from green fluorescent protein (GFP) expressing mice. Resultant chimeras exhibited a significant decline in alveolar macrophage numbers within 72 h, modest influx of neutrophils in the lungs at 14 days, and repopulation of the lungs by alveolar macrophages of bone marrow origin by 28 days. Neutrophil influx and alveolar macrophage turnover were prevented when 1 cm thick lead shields were used to protect the lungs during radiation, such that 8 weeks after transplantation less than 30% of alveolar macrophages were of donor origin. Lung-shielded mice achieved a high level of bone marrow engraftment with greater than 95% of circulating leukocytes expressing GFP. In addition, their response to intratracheal lipopolysaccharide was similar to non-transplanted mice. We describe a model whereby lead shields protect resident cell populations in the lungs from radiation during bone marrow transplantation but permit full bone marrow engraftment. This system may be applicable to other organ systems in which protection from radiation during bone marrow transplantation is desired.

Because the lungs are exposed to airborne hazardous materials, alveolar macrophages (AMs) play a major role in defending against the exposure to various noxious chemical substances. In this study, we reviewed magnetometric investigations of the effects of various chemicals on the lungs and AMs. Magnetometry, using magnetite as an indicator, was used to evaluate the effects of certain chemicals on the lung and AMs. A rapid decrease of the remanent magnetic field after the cessation of external magnetization, a phenomenon called relaxation, was impaired when the lungs and macrophages were exposed to toxic substances. The delayed in vivo relaxation observed in the lungs exposed to magnetite and gallium arsenide was almost identical to the in vitro relaxation observed in the AMs exposed to the same materials. Delayed relaxation was observed in the AMs exposed to silica dust; various fibers, such as chrysotile and some man-made mineral fibers; and toxic arsenic and cadmium compounds. The extracellular release of lactate dehydrogenase activity was found in the AMs exposed to the chemicals. Relaxation is attributed to the cytoskeleton-driven rotation of phagosomes containing magnetite. While the exact mechanism of delayed relaxation due to exposure to harmful chemicals remains to be clarified, cell magnetometry appears to be useful for the safety screening of chemical substances.

Inhaled particles reaching the alveolar walls have the potential to cross the blood-gas barrier and enter the blood stream. Experimental evidence of pulmonary dosimetry, however, cannot be explained by current whole lung dosimetry models. Numerical and experimental studies shed some light on the mechanisms of particle transport, but realistic geometries have not been investigated. In this study, a three dimensional expanding model including two generations of respiratory bronchioles and five terminal alveolar sacs was created from a replica human lung cast. Flow visualization techniques were employed to quantify the fluid flow while utilizing streamlines to evaluate recirculation. Pathlines were plotted to track the fluid motion and estimate penetration depth of inhaled air. This study provides evidence that the two generations immediately proximal to the terminal alveolar sacs do not have recirculating eddies, even for intense breathing. Results of Peclet number calculations indicate that substantial convective motion is present in vivo for the case of deep breathing, which significantly increases particle penetration into the alveoli. However, particle diffusion remains the dominant mechanism of particle transport over convection, even for intense breathing because inhaled particles do not reach the alveolar wall in a single breath by convection alone. Examination of the velocity fields revealed significant uneven ventilation of the alveoli during a single breath, likely due to variations in size and location. This flow field data, obtained from replica model geometry with realistic breathing conditions, provides information to better understand fluid and particle behavior in the acinus region of the lung.

A series of investigations were carried out including epidemiology, etiology and pathology on hemorrhagic pneumonia in Moschus sifanicus, which had prevailed in Xinglong Mountain National Nature Reserve District in Gansu province of China. The results indicated that the prevalence of this disease could be correlated with local humidity in Xinglong Mountain in Gansu province of China. The disease is caused by single infection of Pasteurella multocida or mix of P. multocida, Escherichia coli and Pseudomonas aeruginosa, and is a contagious disease. The pathological changes were mainly manifested in the vessel wall of bronchia and bronchiole appeared congested, bleeding, edemic with infiltration of inflammatory cells, mucosa of bronchiole degenerates, with the presence of necrosis and exfoliation, pulmonary alveolus generated suppuration, disaggregation and necrosis. It was concluded that the diseases are mainly caused by local bacteria and affected M. sifanicus finally die of hemorrhagic or purulent, necrotic pneumonia.

Recent studies of primate models suggest that wild-type measles virus (MV) infects immune cells located in the airways before spreading systemically, but the identity of these cells is unknown. To identify cells supporting primary MV infection, we took advantage of mice expressing the MV receptor human signaling lymphocyte activation molecule (SLAM, CD150) with human-like tissue specificity. We infected these mice intranasally (IN) with a wild-type MV expressing green fluorescent protein. One, two, or three days after inoculation, nasal-associated lymphoid tissue (NALT), the lungs, several lymph nodes (LNs), the spleen, and the thymus were collected and analyzed by microscopy and flow cytometry, and virus isolation was attempted. One day after inoculation, MV replication was documented only in the airways, in about 2.5% of alveolar macrophages (AM) and 0.5% of dendritic cells (DC). These cells expressed human SLAM, and it was observed that MV infection temporarily enhanced SLAM expression. Later, MV infected other immune cell types, including B and T lymphocytes. Virus was isolated from lymphatic tissue as early as 2 days post-IN inoculation; the mediastinal lymph node was an early site of replication and supported high levels of infection. Three days after intraperitoneal inoculation, 1 to 8% of the mediastinal LN cells were infected. Thus, MV infection of alveolar macrophages and subepithelial dendritic cells in the airways precedes infection of lymphocytes in lymphatic organs of mice expressing human SLAM with human-like tissue specificity.

Diffuse alveolar hemorrhage is a bleeding originating from the pulmonary acinus. Number of causes are possible, that can be divided in immune and non immune causes. Immune mediated diffuse alveolar hemorrhages are mainly due to small vessels vasculitis (Wegener granulomatosis, microscopic polyangiitis), systemic lupus erythematosus and antiglomerular basement membrane antibody disease. Early immunosuppressive treatment is required, mostly with pulse methylprednisolone and cyclophosphamide. Plasmapheresis are added in antiglomerular basement membrane antibody disease and refractory systemic lupus erythematosus. Non immune mediated diffuse alveolar hemorrhages are mainly due to cardiac failure, severe dyscrasia and idiopathic diffuse alveolar hemorrhage. Barotrauma, cancer microangiopathy, toxic or drug-induced diffuse alveolar hemorrhage are other rare causes. Whatever is the cause, diffuse alveolar hemorrhage is an emergency associated with an intrahospital mortality rate of approximately 20 percent.

The value of Y-body study for assessment of haemopoietic engraftment was analyzed in 50 consecutive patients submitted to allogeneic bone marrow transplantation (BMT) (sex-matched in 28 cases, sex-mismatched in 22). The study was performed weekly on bone marrow and peripheral blood smears in all cases, and alveolar macrophages were also studied in 15 patients in whom bronchoalveolar lavage was carried out because of concurrent respiratory disturbances. The analysis was performed blindly by 2 independent observers. In both sex-matched and sex-mismatched cases there was an absolute concordance between recipient and donor Y-body results, as well as with the simultaneous cytogenetic study. The engraftment of erythroid and granulopoietic lines was documented at day +14 in all cases of sex-mismatched BMT, whereas megakaryocyte and lymphocyte take was demonstrated at d +21. On the other hand, the results from alveolar macrophages were in accordance with those obtained in the simultaneous study of bone marrow precursors after BMT. The above results indicate that Y-body analysis is a simple and useful tool for the demonstration of bone marrow take in sex-mismatched BMT.

Isolated pulmonary involvement in Goodpasture's syndrome is exceptionally described. We report a 36-year-old woman with pulmonary haemorrhage and review 28 additional cases of the literature. In fact, these patients had often mild urine abnormalities and constant glomerular lesions. Antiglomerular basement membrane antibodies testing should be systematically ordered in patients presenting with alveolar haemorrhage. Goodpasture's syndrome without renal abnormality could be an early stage of the disease with a better prognosis.

The aim of this study was to characterize factor(s) in rat bronchoalveolar lavage fluid (BALF) that enhance(s) insulin transport across primary rat alveolar epithelial cell monolayers (RAECM) in primary culture. BALF was concentrated 7.5-fold using the Centricon device and the retentate was used to characterize the factor(s) involved in enhancing apical-to-basolateral transport of intact 125I-insulin across various epithelial cell monolayers. These factor(s) enhanced transport of intact insulin across type II cell-like RAECM (3-fold increase) and type I cell-like RAECM (2-fold increase), but not across Caco-2 or MDCK cell monolayers. The insulin transport-enhancing factor(s) were temperature- and trypsin-sensitive. The mechanism of enhancement did not seem to involve paracellular transport or fluid-phase endocytosis, since fluxes of sodium fluorescein and FITC-dextran (70 kDa) were not affected by the factor(s) in the apical bathing fluid. BALF enhancement of intact 125I-insulin transport was abolished at 4 degrees C and in the presence of monensin, suggesting involvement of transcellular pathways. Sephacryl S-200 purification of BALF retentate, followed by LC-MS/MS, indicated that the high molecular weight (>100 kDa) fractions (which show some homology to alpha-1-inhibitor III, murinoglobulin gamma 2, and pregnancy-zone protein) appear to facilitate transcellular transport of insulin across RAECM.

A major route of transmission ofVisna/maedi virus(VMV), an ovine lentivirus, is thought to be via the respiratory tract, by inhalation of either cell-free or cell-associated virus. In previous studies, we have shown that infection via the lower respiratory tract is much more efficient than via upper respiratory tissues (T. N. McNeilly, P. Tennant, L. Lujan, M. Perez, and G. D. Harkiss, J. Gen. Virol.88:670-679, 2007). Alveolar macrophages (AMs) are prime candidates for the initial uptake of virus in the lower lung, given their in vivo tropism for VMV, abundant numbers, location within the airways, and role in VMV-induced inflammation. Furthermore, AMs are the most likely cell type involved in the transmission of cell-associated virus. In this study, we use an experimental in vivo infection model that allowed the infection of specific segments of the ovine lung. We demonstrate that resident AMs are capable of VMV uptake in vivo and that this infection is associated with a specific up-regulation of AM granulocyte-macrophage colony-stimulating factor mRNA expression (P< 0.05) and an increase in bronchoalveolar lymphocyte numbers (P< 0.05), but not a generalized inflammatory response 7 days postinfection. We also demonstrate that both autologous and heterologous VMV-infected AMs are capable of transmitting virus after lower, but not upper, respiratory tract instillation and that this transfer of virus appears not to involve the direct migration of virus-infected AMs from the airspace. These results suggest that virus is transferred from AMs into the body via an intermediate route. The results also suggest that the inhalation of infected AMs represents an additional mechanism of virus transmission.

TiO2 ultrafine particles are used as photo-catalysis. When ultrafine particles are exposed to hosts, they are invaded in alveolar, transferred to organs through blood vessels and may express biological effects. We administered TiO2 ultra-fine particles (5 nm, 100 nm) intratracheally to mice, and collected whole blood and removed organs (liver, lung, kidney, spleen and brain) after 1, 4 and 24 hours. The quantity of Ti in the blood and these organs was analyzed by PIXE (Particle Induced X-Ray Emission) or ICP/MS (Inductively Coupled Plasma-Mass Spectrometry). Compared to control mice, the quantity of Ti in the exposed mice was not different. Consequently, we observed the solution of dissolved TiO2 ultrafine particles by Scanning Electron Microscope, and observed the particles which aggregated. That diameter was about 1 microm. We concluded that the particles had aggregated before administration to mice, so they didn't invade the blood vessels or organs from the pulmonary alveolus in the lung.

In previous studies we showed that aCryptococcus neoformansmutant lacking glucosylceramide (Δgcs1) is avirulent and unable to reach the brain when it is administered intranasally into an immunocompetent mouse and is contained in a lung granuloma. To determine whether granuloma formation is key for containment ofC. neoformansΔgcs1, we studied the role ofC. neoformansglucosylceramide in a T- and NK-cell-immunodeficient mouse model (Tgε26) in which alveolar macrophages (AMs) are not activated and granuloma formation is not expected. The results show that Tgε26 mice infected with Δgcs1do not produce a lung granuloma and that the Δgcs1mutant proliferates in the lungs and does disseminate to the brain, although its virulence phenotype is dramatically reduced. Since Δgcs1can grow only in acidic niches, such as the phagolysosome of AMs, and not in neutral or alkaline environments, such as the extracellular spaces, we hypothesize that in immunodeficient mice Δgcs1proliferates inside AMs. Indeed, we found that depletion of AMs significantly improved Tgε26 mouse survival and decreased the dissemination of Δgcs1cells to the central nervous system. Thus, these results suggest that the growth of Δgcs1in immunodeficient mice is maintained within AMs. This study highlights the hypothesis that AMs may exacerbateC. neoformansinfection in conditions in which there is severe host immunodeficiency.

Objectives: A validated microbiological assay was used to measure concentrations of iclaprim (AR-100) in plasma, bronchial mucosa (BM), alveolar macrophages (AM) and epithelial lining fluid (ELF) after a single 1.6 mg/kg intravenous 60 min iv infusion of iclaprim. Methods: Male volunteers were randomly allocated to three nominal sampling time intervals 1-2 h (Group A), 3-4 h (Group B) and 5.5-7.0 h (Group C) after the start of the drug infusion. Results: Mean iclaprim concentrations in plasma, BM, AM and ELF, respectively, were for Group A 0.59 mg/L (SD 0.18), 0.51 mg/kg (SD 0.17), 24.51 mg/L (SD 21.22) and 12.61 mg/L (SD 7.33); Group B 0.24mg/L (SD 0.05), 0.35 mg/kg (SD 0.17), 7.16 mg/L (SD 1.91) and 6.38mg/L (SD 5.17); and Group C 0.14 mg/L (SD 0.05), no detectable level in BM, 5.28 mg/L (SD 2.30) and 2.66 mg/L (SD 2.08). Conclusions: Iclaprim concentrations in ELF and AM exceeded the MIC 90 for penicillin-susceptible Streptococcus pneumoniae (MIC 90 0.06mg/L), penicillin-intermediate S. pneumoniae (MIC 90 2mg/L), penicillin-resistant S. pneumoniae (MIC 90 4 mg/L) for 7,7 and 4 h, respectively, and Chlamydia pneumoniae (MIC 90 0.5mg/L) for 7h. Mean iclaprim concentrations in ELF exceeded the MIC 90 for Haemophilus influenzae (MIC 90 4 mg/L) and Moraxella catarrhalis (MIC 90 8 mg/L) for up to 4 and 2 h, respectively; in AM the MIC 90 was exceeded for up to 7 h. Furthermore, the MIC 90 for methicillin-resistant Staphylococcus aureus of 0.12 mg/L was exceeded at all sites for up to 7 h. These data suggest that iclaprim reaches lung concentrations that should be effective in the treatment of community-acquired pneumonia.

Pneumocystis cariniiis an opportunistic fungal pathogen that causes life-threatening pneumonia in immunocompromised individuals. Infants appear to be particularly susceptible toPneumocystispulmonary infections. We have previously demonstrated that there is approximately a 3-week delay in the clearance ofPneumocystisorganisms from pup mouse lungs compared to that in adults. We have further shown that there is approximately a 1-week delay in alveolar macrophage activation in pups versus adult mice. Alveolar macrophages are the primary effector cells responsible for the killing and clearance ofPneumocystis, suggesting that pup alveolar macrophages may be involved in the delayed clearance of this organism. Alveolar macrophages cultured in vitro withPneumocystisalone demonstrate little to no activation, as indicated by a lack of cytokine production. However, when cultured with lipopolysaccharide (LPS) or zymosan, cytokine production was markedly increased, suggesting that pup alveolar macrophages are specifically unresponsive toPneumocystisorganisms rather than being intrinsically unable to become activated. Furthermore, pup mice treated with aerosolized, heat-killedEscherichia coliin vivo were able to clearPneumocystismore efficiently than were control mice. Together, these data suggest that while pup alveolar macrophages are unresponsive toP. cariniif. sp.murisorganisms, they are capable of activation by heat-killedE. coliin vivo, as well as LPS and zymosan in vitro. The lack of response of pup mice toP. cariniif. sp.murismay reflect protective mechanisms specific to the developing pup lung, but ultimately it results in insufficient clearance ofPneumocystisorganisms.

The functional capacity of alveolar macrophages (AM) in human immunodeficiency virus (HIV)-infected patients with pulmonary tuberculosis (TB) is not completely understood. To investigate the capacity of AM to mediate inflammatory responses, we obtained AM from human subjects by bronchoalveolar lavage (BAL) and studied the cells ex vivo. We compared AM from HIV-infected patients with suspected pulmonary TB to AM from healthy, HIV-negative controls for their capacity to produce TNF-alpha or 1L-6 spontaneously and upon stimulation with lipopolysaccharide (LPS). Cytokine-producing cells were identified by macrophage markers and intracellular cytokine staining and flow cytometry. A higher proportion of AM from patients with microbiologically confirmed pulmonary TB than patients with probable TB or controls spontaneously expressed TNF-a shortly after isolation (geometric means: 38.5%, 23.7% and 15.8%, respectively), suggesting endogenous cytokine production. The proportions of AM spontaneously expressing TNF-a positively correlated with peripheral blood CD4(+) T-lymphocyte counts in patients (partial r = 0.60, p =: 0.003) but not controls. Stimulation with LPS resulted in a significant increase in the proportions of TNF-alpha and 1L-6-positive AM from patients and controls (p < 0.01). Bronchoalveolar lavage fluid (BALF) from confirmed TB patients also contained higher concentrations of the inflammatory cytokines predominantly produced by macrophages, IL=6 and IL-8, than controls (geometric mean cytokine concentrations per gram of BALE albumin were 1291 pg/g vs. 115 pg/g, p = 0.03 for IL-6 and 4739 pg/g vs. 704 pg/g, p = 0.03 for IL-8). We concluded that.AM from HIV-infected patients with pulmonary TB produced and released inflammatory cytokines in vivo and retained their innate ability to respond to stimulation by LPS. (C) 2007 Elsevier Masson SAS. All rights reserved.

Amiodarone (AMI) is a potent antiarrhythmic agent; however, its clinical use is limited due to numerous side effects. In order to investigate the structure--cytotoxicity relationship, AMI analogues were synthesized, and then, using rabbit alveolar macrophages, were tested for viability and for the ability to interfere with the degradation of surfactant protein A (SP-A) and with the accumulation of an acidotropic dye. Our data revealed that modification of the diethylamino-beta-ethoxy group of the AMI molecule may affect viability, the ability to degrade SP-A and vacuolation differently. In particular, PIPAM (2d), an analogue with a piperidyl moiety, acts toward the cells in a similar manner to AMI, but is less toxic. Thus, it would be possible to reduce the cytotoxicity of AMI by modifying its chemical structure.

The early influx of neutrophils to the site of infection may be an important step in host resistance against Mycobacterium tuberculosis . In this study, we investigated the effect of M. tuberculosis infection on the ability of guinea pig neutrophils to produce interleukin-8 (IL-8; CXCL8) and tumor necrosis factor alpha (TNF-α) and to activate alveolar macrophages. Neutrophils and alveolar macrophages were isolated from naïve guinea pigs, cultured together or alone, and infected with virulent M. tuberculosis for 3, 12, and 24 h. IL-8 protein production in cocultures, as measured by using an enzyme-linked immunosorbent assay, was found to be additive at 24 h and significantly greater in M. tuberculosis -infected cocultures than in uninfected cocultures and in cultures of the infected neutrophils or macrophages alone. The IL-8 mRNA levels, determined by real-time reverse transcription-PCR, were elevated at 24 h in infected cocultures and infected cells cultured alone. In order to elucidate the contributions of neutrophils and their soluble mediators to the activation of alveolar macrophages, neutrophils and alveolar macrophages were cultured in a contact-independent manner by using a Transwell insert system. Neutrophils were infected with virulent M. tuberculosis in the upper wells, and alveolar macrophages were cultured in the lower wells. The release of hydrogen peroxide from alveolar macrophages exposed to soluble products from infected neutrophils was significantly increased compared to that from unexposed alveolar macrophages. Significant up-regulation of IL-1β and TNF-α mRNA levels in alveolar macrophages was observed at 24 and 30 h, respectively, compared to those in cells not exposed to soluble neutrophil products. Treatment with anti-guinea pig TNF-α polyclonal antibody completely abolished the response of alveolar macrophages to neutrophil products. This finding suggests that TNF-α produced by infected neutrophils may be involved in the activation of alveolar macrophages and hence may contribute to the containment of M. tuberculosis infection during the early period of infection.

Influenza infection was induced in white mice by intranasal inoculation of the virus A/Aichi/2/68 (H3N2). The lung protease and the protease-inhibitory activities were followed for 9 days after infection. The intranasal application of a polyphenol-rich extract (PC) isolated from Geranium sanguineum L. induced a continuous rise in the anti-protease activity but did not cause substantial changes in the lung protease activity of healthy mice. Influenza virus infection triggered a slight reduction in protease activity in the lungs at 5 and 48 h post infection (p.i.) and a marked increase at 24 h and 6 day p.i. Protease inhibition in the lungs was reduced at 24 and 48 h p.i. and an increase was observed at 5 h and 6 and 9 days p.i. PC treatment brought both activities to normal levels. The restoration of the examined parameters was consistent with a prolongation of mean survival time and reduction of mortality rate, infectious virus titre and lung consolidation. PC reinstated superoxide production by alveolar macrophages and increased their number in virus-infected mice. The favourable effect on the protease and the protease-inhibitory activities in the lungs of influenza-virus-infected mice apparently contributes to the overall protective effect of PC in the murine experimental influenza A/Aichi infection. The antiviral effect of the individual constituents was evaluated.

Micron-sized particles inhaled into the respiratory system can traverse the airway tree and deposit on the walls of the pulmonary alveoli. The fate of these particles can be measured by their propagation depth, wall deposition rate, and time to impaction. These three quantities depend on various physical parameters including particle size, alveolar geometry, tissue properties, and breathing patterns. In this study, we develop a 2-D fluid-structure computational model of alveolar dynamics to quantify how these parameters influence particle transport in the deep lung. The computational model simulates negative pressure breathing conditions in which applied tissue forces deform the lung parenchyma and produce oscillatory flow within the alveoli. Alveolar flow patterns are used to calculate the trajectories of micron-sized particles (i.e. 0.1 – 5 μ m ) by solving the Langevin equation, which contains a stochastic Brownian force term. As a result, these fluid-structure models can be used to investigate how tissue mechanical properties and breathing patterns influence deep-lung flow fields and particle dynamics. Results indicate that Brownian diffusion dominates the transport of small particles ( d p 0.5 μ m ) , while gravitational sedimentation dominates the transport of large particles ( d p > 1 μ m ) . Mid-size particles ( 0.5 ⩽ d p ⩽ 1 μ m ) experience slower diffusion and slower sedimentation transport, so their time to impaction is maximized. Stiffer tissues produce higher particle impaction rates under microgravity conditions while tissue viscosity has negligible effects on particle dynamics. We also compare our computational results to previously published experimental studies and conclude that targeting inhaled particles to the deep lungs increases whole-lung deposition efficiencies because diffusion and sedimentation are efficient transport mechanisms in the small, distal structures.