Association between respiratory mechanics and autonomic function in morbid obesity.

This study aimed to investigate the association between respiratory mechanics and autonomic modulation in morbidly obese patients. We evaluated 10 morbidly obese subjects (BMI=52.9±11.2kg/m(2)), aged 23-58 years. Assessment of respiratory mechanics was done by the forced oscillation technique (FOT), and cardiovascular autonomic function was recorded by heart rate variability analysis (HRV). The Pearson correlation coefficient was used to test the associations between respiratory mechanics and HRV variables. There were associations between the standard deviation of all RR intervals (SDNN) and airway resistance (Rm) (r=-0.82; p=0.004), SDNN and respiratory system resistance (R0) (r=-0.79; p=0.006), root mean square of successive differences between adjacent normal RR intervals (rMSSD) and respiratory system resistance (R5) (r=-0.643; p=0.0451), rMSSD and R0 (r=-0.64; p=0.047), and rMSSD and Rm (r=-0.658; p=0.039). We concluded that the airway and respiratory system resistances are negatively associated with parasympathetic activity in patients with morbid obesity.

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.

Recruitment maneuver: RAMP versus CPAP pressure profile in a model of acute lung injury.

We examined whether recruitment maneuvers (RMs) with gradual increase in airway pressure (RAMP) provide better outcome than continuous positive airway pressure (CPAP) in paraquat-induced acute lung injury (ALI). Wistar rats received saline intraperitoneally (0.5 mL, CTRL) or paraquat (15 mg/kg, ALI). Twenty-four hours later lung mechanics [static elastance, viscoelastic component of elastance, resistive, viscoelastic and total pressures] were determined before and after recruitment with 40cmH2O CPAP for 40s or 40-s-long slow increase in pressure up to 40cmH2O (RAMP) followed by 0 or 5 cmH2O PEEP. Fractional area of alveolar collapse and PCIII mRNA were determined. All mechanical parameters and the fraction area of alveolar collapse were higher in ALI compared to CTRL. Only RAMP-PEEP maneuver significantly improved lung mechanics and decreased PCIII mRNA expression (53%) compared with ALI, while both RMs followed by PEEP decreased alveolar collapse. In conclusion, in the present experimental ALI model, RAMP followed by 5cm H2O PEEP yields a better outcome.

Does the use of recombinant AAV5 in pulmonary gene therapy lead to lung damage?

This study investigated whether repeated administration of recombinant adeno-associated virus type 5 (rAAV5) to the airways induces inflammatory processes in the lungs of BALB/c-mice, with mechanical and histologic changes. Saline was instilled intratracheally in the control group, and rAAV5-green fluorescence protein (GFP) (4x10(11)particles) in the virus group (VR). These groups were subdivided into four subgroups: one dose analyzed 3 weeks later (VR1d3w) and two doses analyzed 1 (VR2d1w), 2 (VR2d2w) and 3 weeks (VR2d3w) after the second dose. Lung morphometry, mechanical parameters, airway responsiveness, rAAV5-GFP transduction and the expression of inflammatory cytokines were investigated. No significant differences in lung mechanics, airway responsiveness, and morphometry were observed. Re-administration of rAAV5 vector resulted in a decrease in GFP mRNA expression in the VR2d3w group. There was no evidence of inflammatory response or apoptosis in any group. rAAV5 did not induce an inflammatory process, mechanical or morphometric changes in the lungs. AAV5 may be an appropriate vector for lung gene therapy.

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.

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.

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.

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.

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 æg ovalbumin (OVA, ip) on 7 alternate days, and after day 40 they were challenged with three intratracheal instillations of 20 æg 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 percent, 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.

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.

The central role of Fas-ligand cell signaling in inflammatory lung diseases.

Following inflammation and injury in the lung, loss of epithelial cell precursors could determine the balance between tissue regeneration and fibrosis. This review discusses evidence that proapoptotic Fas-Fas ligand (FasL) signaling plays a central role in pulmonary inflammation, injury and fibrosis. FasL signaling induces inflammatory apoptosis in epithelial cells and alveolar macrophages, with concomitant IL-1 beta and chemokine release, leading to neutrophil infiltration. FasL signaling plays a critical role in models of acute lung injury, idiopathic pulmonary fibrosis and silicosis; blockade of Fas-FasL interactions either prevents or attenuates pulmonary inflammation and fibrosis. Serologic and immunohistochemical studies in patients support a major pathogenic role of Fas and FasL molecules in inflammatory lung diseases. Identification of the pathogenic role of FasL could facilitate the discovery of more effective treatments for currently untreatable inflammatory lung diseases.

Toxicity of a cyanobacterial extract containing microcystins to mouse lungs

Toxic cyanobacteria in drinking water supplies can cause serious public health problems. In the present study we analyzed the time course of changes in lung histology in young and adult male Swiss mice injected intraperitoneally (ip) with a cyanobacterial extract containing the hepatotoxic microcystins. Microcystins are cyclical heptapeptides quantified by ELISA method. Ninety mice were divided into two groups. Group C received an injection of saline (300 µl, ip) and group Ci received a sublethal dose of microcystins (48.2 µg/kg, ip). Mice of the Ci group were further divided into young (4 weeks old) and adult (12 weeks old) animals. At 2 and 8 h and at 1, 2, 3, and 4 days after the injection of the toxic cyanobacterial extract, the mice were anesthetized and the trachea was occluded at end-expiration. The lungs were removed en bloc, fixed, sectioned, and stained with hematoxylin-eosin. The percentage of the area of alveolar collapse and the number of polymorphonuclear (PMN) and mononuclear cell infiltrations were determined by point counting. Alveolar collapse increased from C to all Ci groups (123 to 262 percent) independently of time, reaching a maximum value earlier in young than in adult animals. The amount of PMN cells increased with time of the lesion (52 to 161 percent). The inflammatory response also reached the highest level earlier in young than in adult mice. After 2 days, PMN levels remained unchanged in adult mice, while in young mice the maximum number was observed at day 1 and was similar at days 2, 3, and 4. We conclude that the toxins and/or other cyanobacterial compounds probably exert these effects by reaching the lung through the blood stream after ip injection.

Toxicity of a cyanobacterial extract containing microcystins to mouse lungs.

Toxic cyanobacteria in drinking water supplies can cause serious public health problems. In the present study we analyzed the time course of changes in lung histology in young and adult male Swiss mice injected intraperitoneally (ip) with a cyanobacterial extract containing the hepatotoxic microcystins. Microcystins are cyclical heptapeptides quantified by ELISA method. Ninety mice were divided into two groups. Group C received an injection of saline (300 microl, ip) and group Ci received a sublethal dose of microcystins (48.2 microg/kg, ip). Mice of the Ci group were further divided into young (4 weeks old) and adult (12 weeks old) animals. At 2 and 8 h and at 1, 2, 3, and 4 days after the injection of the toxic cyanobacterial extract, the mice were anesthetized and the trachea was occluded at end-expiration. The lungs were removed en bloc, fixed, sectioned, and stained with hematoxylin-eosin. The percentage of the area of alveolar collapse and the number of polymorphonuclear (PMN) and mononuclear cell infiltrations were determined by point counting. Alveolar collapse increased from C to all Ci groups (123 to 262%) independently of time, reaching a maximum value earlier in young than in adult animals. The amount of PMN cells increased with time of the lesion (52 to 161%). The inflammatory response also reached the highest level earlier in young than in adult mice. After 2 days, PMN levels remained unchanged in adult mice, while in young mice the maximum number was observed at day 1 and was similar at days 2, 3, and 4. We conclude that the toxins and/or other cyanobacterial compounds probably exert these effects by reaching the lung through the blood stream after ip injection.

Respiratory mechanics and pleural remodelling in pleurodesis induced by barium sulphate.

The aim of this study was to determine whether an intrapleural injection of barium sulphate would produce pleurodesis in rats. Additionally, respiratory mechanics and pleural remodelling were analysed. Single intrapleural injection of barium sulphate (100%) or saline was given to Wistar rats. Respiratory system, lung, and chest wall elastic, resistive and viscoelastic/inhomogeneous pressures were measured by the end-inflation occlusion method at 2 and 30 days after injection. The pleura were examined for gross and histopathological evidence of pleural inflammation and fibrosis, and the underlying lungs were also studied by morphometry. All pulmonary mechanical parameters increased at day 2, but were not different from control at 30 days after injection. Chest wall mechanical parameters did not change. Macroscopic evaluation demonstrated pleural adherence without haemothorax. Histopathologic analysis showed pleural inflammation and fibrosis. There was no alveolar inflammation or fibrosis in both groups. In conclusion, barium sulphate induced pleurodesis with either no changes in respiratory mechanics or lung lesion at day 30.

Effects of propofol on respiratory mechanic and lung histology in normal rats.

BACKGROUND: Propofol is able to reduce airway resistance in lungs with previous airway constriction. The aim of this study was to evaluate the effects of propofol on respiratory mechanics in normal rats and to correlate these parameters with lung histology, to define the sites of action of propofol. METHODS: Sixteen Wistar rats were divided into two groups of eight animals. Rats were sedated (diazepam) and anaesthetized with pentobarbital sodium (C) or propofol (P), and paralysed. Respiratory system, lung, and chest wall resistive, elastic, and viscoelastic/inhomogeneous pressures were computed using the end-inflation occlusion method. RESULTS: Lung resistive pressure was smaller in group P (0.29 kPa (0.05)) than group C (0.37 kPa (0.04)) (P=0.007). The internal diameter of the central airways was greater in group P than C (P=0.01). CONCLUSION: Propofol acts at the airway level decreasing respiratory system and lung impedances as a result of central airway dilation.

Clinical features of panic patients sensitive to hyperventilation or breath-holding methods for inducing panic attacks.

Our aim was to compare the clinical features of panic disorder (PD) patients sensitive to hyperventilation or breath-holding methods of inducing panic attacks. Eighty-five PD patients were submitted to both a hyperventilation challenge test and a breath-holding test. They were asked to hyperventilate (30 breaths/min) for 4 min and a week later to hold their breath for as long as possible, four times with a 2-min interval. Anxiety scales were applied before and after the tests. We selected the patients who responded with a panic attack to just one of the tests, i.e., those who had a panic attack after hyperventilating (HPA, N = 24, 16 females, 8 males, mean age +/- SD = 38.5 +/- 12.7 years) and those who had a panic attack after breath holding (BHPA, N = 20, 11 females, 9 males, mean age +/- SD = 42.1 +/- 10.6 years). Both groups had similar (chi(2) = 1.28, d.f. = 1, P = 0.672) respiratory symptoms (fear of dying, chest/pain discomfort, shortness of breath, paresthesias, and feelings of choking) during a panic attack. The criteria of Briggs et al. [British Journal of Psychiatry, 1993; 163: 201-209] for respiratory PD subtype were fulfilled by 18 (75.0%) HPA patients and by 14 (70.0%) BHPA patients. The HPA group had a later onset of the disease compared to BHPA patients (37.9 +/- 11.0 vs 21.3 +/- 12.9 years old, Mann-Whitney, P < 0.001), and had a higher family prevalence of PD (70.8 vs 25.0%, chi(2) = 19.65, d.f. = 1, P = 0.041). Our data suggest that these two groups--HPA and BHPA patients--may be specific subtypes of PD.

Clinical features of panic patients sensitive to hyperventilation or breath-holding methods for inducing panic attacks

Our aim was to compare the clinical features of panic disorder (PD) patients sensitive to hyperventilation or breath-holding methods of inducing panic attacks. Eighty-five PD patients were submitted to both a hyperventilation challenge test and a breath-holding test. They were asked to hyperventilate (30 breaths/min) for 4 min and a week later to hold their breath for as long as possible, four times with a 2-min interval. Anxiety scales were applied before and after the tests. We selected the patients who responded with a panic attack to just one of the tests, i.e., those who had a panic attack after hyperventilating (HPA, N = 24, 16 females, 8 males, mean age ± SD = 38.5 ± 12.7 years) and those who had a panic attack after breath holding (BHPA, N = 20, 11 females, 9 males, mean age ± SD = 42.1 ± 10.6 years). Both groups had similar (chi² = 1.28, d.f. = 1, P = 0.672) respiratory symptoms (fear of dying, chest/pain disconfort, shortness of breath, paresthesias, and feelings of choking) during a panic attack. The criteria of Briggs et al. [British Journal of Psychiatry, 1993; 163: 201-209] for respiratory PD subtype were fulfilled by 18 (75.0 percent) HPA patients and by 14 (70.0 percent) BHPA patients. The HPA group had a later onset of the disease compared to BHPA patients (37.9 ± 11.0 vs 21.3 ± 12.9 years old, Mann-Whitney, P < 0.001), and had a higher family prevalence of PD (70.8 vs 25.0 percent, chi² = 19.65, d.f. = 1, P = 0.041). Our data suggest that these two groups - HPA and BHPA patients - may be specific subtypes of PD.

Therapeutic potential of a new phosphodiesterase inhibitor in acute lung injury.

The effects of LASSBio596, a phosphodiesterase type-4 and -5 inhibitor, were tested in Escherichia coli lipopolysaccharide (LPS)-induced acute lung injury. Twenty-four BALB/c mice were randomly divided into four groups. In the control group, saline (0.05 mL) was injected intratracheally (i.t.). The LPS group received LPS (10 microg i.t., 0.05 mL). In the LASSBio596 groups, LASSBio596 (10 mg x kg(-1), 0.2 mL) was injected intraperitoneally 1 h before or 6 h after LPS administration. After 24 h, in vivo (lung resistive and viscoelastic pressures, and static and dynamic elastances) and in vitro (tissue resistance, elastance and hysteresivity) pulmonary mechanics, lung morphometry and collagenous fibre content were computed. Neutrophils and tumour necrosis factor (TNF)-alpha levels were evaluated in the bronchoalveolar lavage fluid. LASSBio596 prevented the changes in lung mechanics, and inhibited neutrophilic recruitment, TNF-alpha release, bronchoconstriction, alveolar collapse and the increment of collagen fibre content induced by LPS, independently of the moment of injection. In conclusion, LASSBio596 modulated the lung inflammatory process and had the potential to block fibroproliferation. Thus, agents that inhibit phosphodiesterase 4 and 5 simultaneously may be a useful adjunct therapy for acute lung injury.