Low dose of fine particulate matter (PM2.5) can induce acute oxidative stress, inflammation and pulmonary impairment in healthy mice.

Air pollution is associated with morbidity and mortality induced by respiratory diseases. However, the mechanisms therein involved are not yet fully clarified. Thus, we tested the hypothesis that a single acute exposure to low doses of fine particulate matter (PM2.5) may induce functional and histological lung changes and unchain inflammatory and oxidative stress processes. PM2.5 was collected from the urban area of São Paulo city during 24 h and underwent analysis for elements and polycyclic aromatic hydrocarbon contents. Forty-six male BALB/c mice received intranasal instillation of 30 µL of saline (CTRL) or PM2.5 at 5 or 15 µg in 30 µL of saline (P5 and P15, respectively). Twenty-four hours later, lung mechanics were determined. Lungs were then prepared for histological and biochemical analysis. P15 group showed significantly increased lung impedance and alveolar collapse, as well as lung tissue inflammation, oxidative stress and damage. P5 presented values between CTRL and P15: higher mechanical impedance and inflammation than CTRL, but lower inflammation and oxidative stress than P15. In conclusion, acute exposure to low doses of fine PM induced lung inflammation, oxidative stress and worsened lung impedance and histology in a dose-dependent pattern in mice.

Fas ligand triggers pulmonary silicosis.

We investigated the role of Fas ligand in murine silicosis. Wild-type mice instilled with silica developed severe pulmonary inflammation, with local production of tumor necrosis factor (TNF)-alpha, and interstitial neutrophil and macrophage infiltration in the lungs. Strikingly, Fas ligand-deficient generalized lymphoproliferative disease mutant (gld) mice did not develop silicosis. The gld mice had markedly reduced neutrophil extravasation into bronchoalveolar space, and did not show increased TNF-alpha production, nor pulmonary inflammation. Bone marrow chimeras and local adoptive transfer demonstrated that wild-type, but not Fas ligand-deficient lung macrophages recruit neutrophils and initiate silicosis. Silica induced Fas ligand expression in lung macrophages in vitro and in vivo, and promoted Fas ligand-dependent macrophage apoptosis. Administration of neutralizing anti-Fas ligand antibody in vivo blocked induction of silicosis. Thus, Fas ligand plays a central role in induction of pulmonary silicosis.

Early short-term versus prolonged low-dose methylprednisolone therapy in acute lung injury.

The present study compared the effects of early short-term with prolonged low-dose corticosteroid therapy in acute lung injury (ALI). In total, 120 BALB/c mice were randomly divided into five groups. In the control group, saline was intratracheally (i.t.) instilled. In the ALI group, mice received Escherichia coli lipopolysaccharide (10 microg i.t.). ALI animals were further randomised into four subgroups to receive saline (0.1 mL i.v.) or methylprednisolone (2 mg x kg(-1) i.v.) at 6 h, 24 h or daily (for 7 days, beginning at day 1). At 1, 3 and 8 weeks, in vivo and in vitro lung mechanics and histology (light and electron microscopy), collagen and elastic fibre content, cytokines in bronchoalveolar lavage fluid and the expression of matrix metalloproteinase (MMP)-9 and -2 were measured. In vivo (static elastance and viscoelastic pressure) and in vitro (tissue elastance and resistance) lung mechanics, alveolar collapse, cell infiltration, collagen and elastic fibre content and the expression of MMP-9 and MMP-2 were increased in ALI at 1 week. Methylprednisolone led to a complete resolution of lung mechanics, avoided fibroelastogenesis and the increase in the expression of MMP-9 and MMP-2 independent of steroid treatment design. Thus, early short-term, low-dose methylprednisolone is as effective as prolonged therapy in acute lung injury.

Mechanical action of the intercostal muscles on the ribs.

The external and internal interosseous intercostal muscles were separately stimulated at end-expiratory lung volume in anesthetized dogs. These muscles were all found to elevate the ribs into which they insert. By attaching weights to the ribs, it was determined that the nonlinear compliance of the ribs was responsible for this phenomenon.

Microcrystalline cellulose induces time-dependent lung functional and inflammatory changes.

We determined whether microcrystalline cellulose (MCC), a component of pharmaceutical tablets, induces pulmonary changes. In vivo [resistive and viscoelastic pressures (DeltaP(1) and DeltaP(2)), static elastance (E(L))] and in vitro [tissue resistance (R), elastance (E), and hysteresivity (eta)] lung mechanics, histology, and bronchoalveolar lavage fluid (BALF) were analyzed 3h, 24h, and 3, 15 and 30 days after intratracheal instillation of saline (C) or MCC in BALB/c mice. DeltaP(1) increased at 3h, remaining higher than C until day 3, while E(L) and DeltaP(2) increased only at 24h. At 3 days all mechanical parameters returned to baseline. R and E increased only at 24h. MCC increased alveolar collapse and the number of neutrophils in BALF at 3h, until 3 and 15 days, respectively. At 3 days MCC migrate from the airways into the parenchyma, where they were observed until 30 days. In conclusion, microcrystalline cellulose yielded an acute and self-limited inflammation that impaired lung mechanics.

Mechanics of intercostal space and actions of external and internal intercostal muscles.

It is conventionally considered that because of their fiber orientations, the external intercostal muscles elevate the ribs, whereas the internal interosseous intercostals lower the ribs. The mechanical action of the intercostal muscles, however, has never been studied directly, and the electromyographic observations supporting this conventional thinking must be interpreted with caution. In the present studies, the external and internal interosseous intercostal muscles have been separately stimulated in different interspaces at, above, and below end-expiratory rib cage volume in anesthetized dogs. The axial (cephalo-caudal) displacements of the ribs were measured using linear displacement transducers. The results indicate that when contracting in a single interspace and other muscles are relaxed, both the external and internal intercostals have a net rib elevating action at end-expiratory rib cage volume. This action increases as rib cage volume decreases, but it progressively decreases as rib cage volume increases such that at high rib cage volumes, both the external and internal intercostals lower the ribs. Stimulating the intercostal muscles in three adjacent intercostal spaces simultaneously produced similar directional rib motion results. We conclude that (a) in contrast with the conventional thinking, the external and internal interosseous intercostals acting alone have by and large a similar effect on the ribs into which they insert; (b) this effect is very much dependent on rib cage (lung) volume; and (c) intercostal muscle action is primarily determined by the resistance of the upper ribs to caudad displacement relative to the resistance of the lower ribs to cephalad displacement. The lateral intercostals, however, might be more involved in postural movements than in respiration. Their primary involvement in rotations of the trunk might account for the presence of two differently oriented muscle layers between the ribs.

Mechanical loads modulate tidal volume and lung washout during high-frequency percussive ventilation.

High-frequency percussive ventilation (HFPV) has been proved useful in patients with acute respiratory distress syndrome. However, its physiological mechanisms are still poorly understood. The aim of this work is to evaluate the effects of mechanical loading on the tidal volume and lung washout during HFPV. For this purpose a single-compartment mechanical lung simulator, which allows the combination of three elastic and four resistive loads (E and R, respectively), underwent HFPV with constant ventilator settings. With increasing E and decreasing R the tidal volume/cumulative oscillated gas volume ratio fell, while the duration of end-inspiratory plateau/inspiratory time increased. Indeed, an inverse linear relationship was found between these two ratios. Peak and mean pressure in the model decreased linearly with increasing pulsatile volume, the latter to a lesser extent. In conclusion, elastic or resistive loading modulates the mechanical characteristics of the HFPV device but in such a way that washout volume and time allowed for diffusive ventilation vary agonistically.

Understanding the mechanisms of lung mechanical stress.

Physical forces affect both the function and phenotype of cells in the lung. Bronchial, alveolar, and other parenchymal cells, as well as fibroblasts and macrophages, are normally subjected to a variety of passive and active mechanical forces associated with lung inflation and vascular perfusion as a result of the dynamic nature of lung function. These forces include changes in stress (force per unit area) or strain (any forced change in length in relation to the initial length) and shear stress (the stress component parallel to a given surface). The responses of cells to mechanical forces are the result of the cell's ability to sense and transduce these stimuli into intracellular signaling pathways able to communicate the information to its interior. This review will focus on the modulation of intracellular pathways by lung mechanical forces and the intercellular signaling. A better understanding of the mechanisms by which lung cells transduce physical forces into biochemical and biological signals is of key importance for identifying targets for the treatment and prevention of physical force-related disorders.

Protective effects of phosphodiesterase inhibitors on lung function and remodeling in a murine model of chronic asthma.

The aim of the present study was to compare the efficacy of a novel phosphodiesterase 4 and 5 inhibitor, LASSBio596, with that of dexamethasone in a murine model of chronic asthma. Lung mechanics (airway resistance, viscoelastic pressure, and static elastance), histology, and airway and lung parenchyma remodeling (quantitative analysis of collagen and elastic fiber) were analyzed. Thirty-three BALB/c mice were randomly assigned to four groups. In the asthma group (N = 9), mice were immunized with 10 microg ovalbumin (OVA, ip) on 7 alternate days, and after day 40 they were challenged with three intratracheal instillations of 20 microg OVA at 3-day intervals. Control mice (N = 8) received saline under the same protocol. In the dexamethasone (N = 8) and LASSBio596 (N = 8) groups, the animals of the asthma group were treated with 1 mg/kg dexamethasone disodium phosphate (0.1 mL, ip) or 10 mg/kg LASSBio596 dissolved in dimethyl sulfoxide (0.2 mL, ip) 24 h before the first intratracheal instillation of OVA, for 8 days. Airway resistance, viscoelastic pressure and static elastance increased significantly in the asthma group (77, 56, and 76%, respectively) compared to the control group. The asthma group presented more intense alveolar collapse, bronchoconstriction, and eosinophil and neutrophil infiltration than the control group. Both LASSBio596 and dexamethasone inhibited the changes in lung mechanics, tissue cellularity, bronchoconstriction, as well as airway and lung parenchyma remodeling. In conclusion, LASSBio596 at a dose of 10 mg/kg effectively prevented lung mechanical and morphometrical changes and had the potential to block fibroproliferation in a BALB/c mouse model of asthma.

Corticosteroids in acute respiratory distress syndrome.

Improving the course and outcome of patients with acute respiratory distress syndrome presents a challenge. By understanding the immune status of a patient, physicians can consider manipulating proinflammatory systems more rationally. In this context, corticosteroids could be a therapeutic tool in the armamentarium against acute respiratory distress syndrome. Corticosteroid therapy has been studied in three situations: prevention in high-risk patients, early treatment with high-dose, short-course therapy, and prolonged therapy in unresolving cases. There are differences between the corticosteroid trials of the past and recent trials: today, treatment starts 2-10 days after disease onset in patients that failed to improve; in the past, the corticosteroid doses employed were 5-140 times higher than those used now. Additionally, in the past treatment consisted of administering one to four doses every 6 h (methylprednisolone, 30 mg/kg) versus prolonging treatment as long as necessary in the new trials (2 mg kg(-1) day(-1) every 6 h). The variable response to corticosteroid treatment could be attributed to the heterogeneous biochemical and molecular mechanisms activated in response to different initial insults. Numerous factors need to be taken into account when corticosteroids are used to treat acute respiratory distress syndrome: the specificity of inhibition, the duration and degree of inhibition, and the timing of inhibition. The major continuing problem is when to administer corticosteroids and how to monitor their use. The inflammatory mechanisms are continuous and cyclic, sometimes causing deterioration or improvement of lung function. This article reviews the mechanisms of action of corticosteroids and the results of experimental and clinical studies regarding the use of corticosteroids in acute respiratory distress syndrome.

Pre- and postoperative inspiratory mechanics in ischemic and valvular heart disease.

In 12 mechanically-ventilated, anesthetized, paralyzed patients undergoing cardiac surgery for either coronary bypass (six subjects) or to correct valvular disfunctions, volume, airflow, tracheal, esophageal, and transpulmonary pressures were measured. Respiratory system elastance and resistance were partitioned into lung and chest wall components. Resistances were further split into homogeneous and uneven elements. Measurements were performed prior to thoracotomy and just after rib cage closure. Before surgery, valvular patients had significantly higher elastances and uneven resistances of the respiratory system and lung than those with ischemic heart disease. Postoperatively, the patients presented with an increase in respiratory system and lung elastances, a decrease in pulmonary resistance, and a rise in chest wall resistance. Surgically induced mechanical changes were similar in ischemic and valvular patients.

Expiratory mechanics before and after uncomplicated heart surgery.

In 12 mechanically ventilated anesthetized paralyzed patients undergoing cardiac surgery for either coronary bypass or for correcting valvular dysfunction volume, airflow, tracheal, esophageal, and transpulmonary pressures were measured. Respiratory system elastance and resistance were partitioned into their lung and chest wall components throughout tidal relaxed expiration. Measurements were performed prior to thoracotomy and just after rib cage closure. Before surgery, patients with valvular disease had significantly higher respiratory system and lung elastances and resistances than those with ischemic heart disease. After surgery, patients with valvular disease showed a decrease in respiratory system and lung resistances. Surgery strikingly modified chest wall resistive properties in both groups. Postoperatively, the mechanical properties of the respiratory system were very similar in valvular and ischemic patients.

Effects of thoracotomy on respiratory system, lung, and chest wall mechanics.

Nineteen rats were sedated, anesthetized, paralyzed, and mechanically ventilated. The respiratory, lung, and chest wall elastances (Est-rs, Est-L, Est-w); respiratory system, pulmonary, and chest wall total resistances (Rtot-rs, Rtot-L, Rtot-w); respiratory system, pulmonary, and chest wall initial resistances (Rinit-rs, Rinit-L, Rinit-w); and respiratory system, pulmonary, and chest wall difference resistances (Rdiff-rs, Rdiff-L, Rdiff-w) were determined before and after thoracotomy using the end-inflation occlusion method. Rinit reflects the Newtonian resistances and Rdiff represents the viscoelastic/inhomogeneous pressure dissipations in the system. Rtot = Rinit+Rdiff, ie, total resistance. The animals were submitted to either anterolateral thoracotomy (group A, n = 7), median sternotomy (group B, n = 6), or median sternotomy under PEEP while the lungs were exposed (group C, n = 6). In groups A and B, statistically significant increases in Rdiff-rs significantly augmented Rtot-rs. The former results were entirely secondary to significant increases in Rdiff-L, which naturally raised Rtot, L. Resistance was not altered in group C rats. Thus, anterolateral thoracotomy and median sternotomy increases Rtot-rs as a consequence of augmented Rdiff-L, but this finding could be prevented by the use of PEEP. Est-rs and Est-L increased in the three groups after surgery. Groups D and E were comprised of four animals each. Both underwent median sternotomy and in group E, PEEP was applied. Histopathologic examination of the lungs demonstrated a higher degree of lung collapse in group D.

Volume-assured pressure support ventilation (VAPSV). A new approach for reducing muscle workload during acute respiratory failure.

This study reports the preliminary clinical evaluation of a new mode of ventilation--volume-assured pressure support ventilation (VAPSV)--which incorporates inspiratory pressure support (PSV) with conventional volume-assisted cycles (VAV). This combination optimizes the inspiratory flow during assisted/controlled cycles, reducing the patient's respiratory burden commonly observed during VAV. Different from conventional PSV, VAPSV assures precise control of tidal volume (VT) in unstable patients. Eight patients with acute respiratory failure (ARF) were submitted to assisted ventilation under VAV and VAPSV. Patient's ventilatory workload (evaluated through the pressure-time product, mechanical work per liter of ventilation, and work per minute) and patient's ventilatory drive (occlusion pressure--P0.1) were significantly reduced during VAPSV. This "relief" was more evident among the most distressed patients (p < 0.001), allowing a reduction of more than 60 percent in muscle load, without the need of increasing peak tracheal pressure. Mean inspiratory flow (VT/TI), VT, and effective dynamic compliance were significantly increased during VAPSV, whereas the effective inspiratory impedance decreased. These mechanical advantages of VAPSV allowed a reduction of intrinsic PEEP, whenever it was present. Blood gas values were similar in both periods. We concluded that VAPSV is a promising form of ventilatory support. At the same time that it was able to safely assure a minimum preset VT, VAPSV reduced patient workload and improved synchrony between the patient and the ventilator during ARF.

Suture or prosthetic reconstruction of experimental diaphragmatic defects.

OBJECTIVE: Diaphragmatic reconstruction may cause several respiratory changes. The aims of the present study were to evaluate the respiratory changes induced by two methods of diaphragmatic reconstruction. METHODS: Two groups of rats with an experimental diaphragmatic defect were studied. In one group (n = 5), diaphragmatic resection was followed by stitching together the borders of the wound (SUT); in another group (n = 5), the defect was repaired by suturing in a polytetrafluoroethylene (PTFE) patch. All animals were sedated, anesthetized, paralyzed, and mechanically ventilated. Spirometry, respiratory mechanics, and thoracoabdominal morphometry were evaluated before and after diaphragmatic reconstruction. RESULTS: The suture of the diaphragm significantly decreased FVC and FEV(1), and increased respiratory system, lung, and chest wall static and dynamic elastances and viscoelastic/inhomogeneous pressures in relation to their respective control values. On the other hand, diaphragmatic reconstruction with PTFE increased only respiratory system, lung, and chest wall static elastances. In addition, respiratory system, pulmonary, and chest wall viscoelastic/inhomogeneous pressures and dynamic elastances, as well as respiratory system and lung elastances, were significantly greater in SUT than in PTFE. Lateral diameter at the level of the xiphoid and cephalocaudal pulmonary diameter diminished only in the SUT group. CONCLUSIONS: The reconstruction of the diaphragm with PTFE might be preferred to simple suture for surgical repair of large diaphragmatic defects, at least from a mechanical standpoint.

Respiratory mechanics after prosthetic reconstruction of the chest wall in normal rats.

OBJECTIVE: Prosthetic reconstruction of the chest wall may yield several respiratory changes. Nevertheless, to our knowledge, no comprehensive analysis of respiratory mechanics under this condition has been hitherto performed. METHODS: Respiratory mechanics were evaluated in two groups of rats. In one group (n=8), a polytetrafluoroethylene (PTFE) patch was used; in another group (n=8), a polypropylene mesh (Marlex) associated with methylmethacrylate (PPMM) was employed. All animals were sedated, anesthetized, paralyzed, and mechanically ventilated before and after the prosthetic reconstruction of the chest wall. After airway occlusion at end inspiration, respiratory system, pulmonary, and chest wall resistive pressures (deltaP1rs, deltaP1L, and deltaP1cw, respectively) and viscoelastic/inhomogeneous pressures (deltaP2rs, deltaP2L, and deltaP2cw, respectively) were determined. Respiratory system, lung, and chest wall static (Est(rs), EstL, and Est(cw), respectively), and dynamic elastances (Edyn(rs), EdynL, and Edyn(cw), respectively), and the corresponding delta elastances (deltaE, calculated as Edyn-Est) were also obtained. RESULTS: In both groups, significant increases in deltaP2rs, deltaP2cw, deltaErs, deltaEcw, Est(rs), EstL, and Est(cw) were observed after chest wall reconstruction. However, deltaP2rs, deltaP2cw, deltaErs, deltaEcw, Est(rs), and EstL were significantly higher in the PPMM group than in the PTFE group. CONCLUSIONS: Prosthetic reconstruction of the chest wall yields not only elastic changes, but also there is also an important increase of pressure dissipated against viscoelastic/inhomogeneous segments of the chest wall. Furthermore, taking into account respiratory mechanics, the PTFE patch might be preferred to the PPMM patch.

Association of PEEP with two different inflation volumes in ARDS patients: effects on passive lung deflation and alveolar recruitment.

OBJECTIVE: To assess the effects of the association of positive end-expiratory pressure (PEEP) with different inflation volumes (V(T)'s) on passive lung deflation and alveolar recruitment in ARDS patients. DESIGN: Clinical study using PEEP with two different V(T)'s and analyzing whether passive lung deflation and alveolar recruitment (Vrec) depend on end-inspired (EILV) or end-expired (EELV) lung volume in mechanically ventilated ARDS patients. SETTING: Medical intensive care unit in a university hospital. PATIENTS AND PARTICIPANTS: Six mechanically ventilated consecutive supine patients with ARDS. INTERVENTIONS: Time-course of thoracic volume decay during passive expiration and Vrec were investigated in six ARDS patients ventilated on PEEP with baseline V(T) (V(T),b) and 0.5V(T) (0.5V(T),b), and on zero PEEP (ZEEP) with V(T),b. Time constants of the fast (tau1) and slow (tau2) emptying compartments, as well as resistances and elastances were also determined. MEASUREMENTS AND RESULTS: (a) the biexponential model best fitted the volume decay in all instances. The fast compartment was responsible for 84+/-7 (0.5V(T),b) and 86+/-5% (V(T),b) on PEEP vs 81+/-6% (V(T),b) on ZEEP (P:ns) of the exhaled V(T), with tau1 of 0.50+/-0.13 and 0.58+/-0.17 s vs 0.35+/-0.11 s, respectively; (b) only tau1 for V(T),b on PEEP differed significantly (P < 0.02) from the one on ZEEP, suggesting a slower initial emptying; (c) for the same PEEP, Vrec was higher with a higher volume (V(T)b) than at a lesser one (0.5V(T),b), reflecting the higher V(T). CONCLUSIONS: In mechanically ventilated ARDS patients: (a) the behavior of airway resistance seems to depend on the degree of the prevailing lung distension; (b) alveolar recruitment appears to be more important when higher tidal volumes are used during mechanical ventilation on PEEP; (c) PEEP changes the mechanical properties of the respiratory system fast-emptying compartment.

Flow and volume dependence of pulmonary mechanics in anesthetized cats.

The effects of inspiratory flow rate and inflation volume on pulmonary mechanics were investigated in six anesthetized-paralyzed cats ventilated by constant-flow inflation. Pulmonary mechanics were assessed using the technique of rapid airway occlusion during constant-flow inflation which allows measurement of the intrinsic pulmonary resistance (RLmin) and of the overall "pulmonary flow resistance" (RLmax), which includes the additional pulmonary pressure losses due to time constant inequalities within the lung and/or stress adaptation. We observed that, at fixed inflation volume, 1) RLmin fitted Rohrer's equation, 2) RLmax was higher at low than intermediate flows, and 3) RLmax-RLmin decreased progressively with increasing flow. At fixed flow, RLmax increased, whereas RLmin decreased with increasing volume. We conclude that during eupneic breathing in cats, the pulmonary flow resistance as conventionally measured includes a significant component reflecting stress adaptation.

Chest wall and respiratory system mechanics in cats: effects of flow and volume.

The effects of inspiratory flow rate and inflation volume on the resistive properties of the chest wall were investigated in six anesthetized paralyzed cats by use of the technique of rapid airway occlusion during constant flow inflation. This allowed measurement of the intrinsic resistance (Rw,min) and overall dynamic inspiratory impedance (Rw,max), which includes the additional pressure losses due to time constant inequalities within the chest wall tissues and/or stress adaptation. These results, together with our previous data pertaining to the lung (Kochi et al., J. Appl. Physiol. 64: 441-450, 1988), allowed us to determine Rmin and Rmax of the total respiratory system (rs). We observed that 1) Rw,max and Rrs,max exhibited marked frequency dependence; 2) Rw,min was independent of flow (V) and inspired volume (delta V), whereas Rrs,min increased linearly with V and decreased with increasing delta V; 3) Rw,max decreased with increasing V, whereas Rrs,max exhibited a minimum value at a flow rate substantially higher than the resting range of V; 4) both Rw,max and Rrs,max increased with increasing delta V. We conclude that during resting breathing, flow resistance of the chest wall and total respiratory system, as conventionally measured, includes a significant component reflecting time constant inequalities and/or stress adaptation phenomena.

Frequency characteristics of lung tissue strip during passive stretch and induced pneumoconstriction.

To investigate the frequency-dependent changes of lung tissue mechanics during pneumoconstriction, we studied guinea pig subpleural lung strips submitted to a multisinusoidal deformation composed of five equal-amplitude discrete frequencies ranging between 0.2 and 3.1 Hz. Strips were submitted to graded step stretch changes (SS) and to graded histamine stimulation (HS) in organ bath. Elastance, resistance, and hysteresivity were calculated at each frequency. The model accounting for the relationship between the complex Young's modulus and the angular frequency showed that the constant-phase hypothesis was satisfied in SS condition. However, HS modified all parameters in the model, and the constant-phase hypothesis could be rejected for HS of 10(-5) and 10(-3) M. The hysteresivity time course changed with angular frequency, but differently in the HS and SS conditions. Our results agree with a serial disposition of the connective matrix and contractile system in lung tissue. We conclude that pneumoconstriction induced significant structural changes at the level of the connective matrix.