Lung Mechanics Over the Century: From Bench to Bedside and Back to Bench.

Lung physiology research advanced significantly over the last 100 years. Respiratory mechanics applied to animal models of lung disease extended the knowledge of the workings of respiratory system. In human research, a better understanding of respiratory mechanics has contributed to development of mechanical ventilators. In this review, we explore the use of respiratory mechanics in basic science to investigate asthma and chronic obstructive pulmonary disease (COPD). We also discuss the use of lung mechanics in clinical care and its role on the development of modern mechanical ventilators. Additionally, we analyse some bench-developed technologies that are not in widespread use in the present but can become part of the clinical arsenal in the future. Finally, we explore some of the difficult questions that intensive care doctors still face when managing respiratory failure. Bringing back these questions to bench can help to solve them. Interaction between basic and translational science and human subject investigation can be very rewarding, as in the conceptualization of "Lung Protective Ventilation" principles. We expect this interaction to expand further generating new treatments and managing strategies for patients with respiratory disease.

Nonlinear Flow Sensor Calibration with an Accurate Syringe.

Flow sensors are required for monitoring patients on mechanical ventilation and in respiratory research. Proper calibration is important for ensuring accuracy and can be done with a precision syringe. This procedure, however, becomes complex for nonlinear flow sensors, which are commonly used. The objective of the present work was to develop an algorithm to allow the calibration of nonlinear flow sensors using an accurate syringe. We first noticed that a power law equation could properly fit the pressure-flow relationship of nonlinear flow sensors. We then developed a software code to estimate the parameters for this equation using a 3 L syringe (calibration syringe). Finally, we tested the performance of a calibrated flow sensor using a different 3 L syringe (testing syringe) and a commercially available spirometer. After calibration, the sensor had a bias ranging from −1.7% to 3.0% and precision from 0.012 L to 0.039 L for volumes measured with the 3 L testing syringe. Calibrated sensor performance was at least as good as the commercial sensor. This calibration procedure can be done at the bedside for both clinical and research purposes, therefore improving the accuracy of nonlinear flow sensors.

Impact of Time on Fluid Resuscitation with Hypertonic Saline (NaCl 7.5%) in Rats with LPS-Induced Acute Lung Injury.

Acute lung injury (ALI) is a common complication associated with septic shock that directly influences the prognosis of sepsis patients. Currently, one of the main supportive treatment modalities for septic shock is fluid resuscitation. The use of hypertonic saline (HS: 7.5% NaCl) for fluid resuscitation has been described as a promising therapy in experimental models of sepsis-induced ALI, but it has failed to produce similar results in clinical practice. Thus, we compared experimental timing versus clinical timing effectiveness (i.e., early vs. late fluid resuscitation) after the inflammatory scenario was established in a rat model of bacterial lipopolysaccharide-induced ALI. We found that late fluid resuscitation with hypertonic saline (NaCl 7.5%) did not reduce the mortality rates of animals compared with the mortality late associated with early treatment. Late fluid resuscitation with both hypertonic and normal saline increased pulmonary inflammation, decreased pulmonary function, and induced pulmonary injury by elevating metalloproteinase-2 and metalloproteinase-9 activity and collagen deposition in the animals, unlike early treatment. The animals with lipopolysaccharide-induced ALI that received late resuscitation with any kind of fluids demonstrated aggravated pulmonary injury and respiratory function. Moreover, we showed that the therapeutic window for a beneficial effect of fluid resuscitation with hypertonic saline is very narrow.

Hypertonic Saline (NaCl 7.5%) Reduces LPS-Induced Acute Lung Injury in Rats.

Acute respiratory distress syndrome (ARDS) is the most severe lung inflammatory manifestation and has no effective therapy nowadays. Sepsis is one of the main illnesses among ARDS causes. The use of fluid resuscitation is an important treatment for sepsis, but positive fluid balance may induce pulmonary injury. As an alternative, fluid resuscitation with hypertonic saline ((HS) NaCl 7.5%) has been described as a promising therapeutical agent in sepsis-induced ARDS by the diminished amount of fluid necessary. Thus, we evaluated the effect of hypertonic saline in the treatment of LPS-induced ARDS. We found that hypertonic saline (NaCl 7.5%) treatment in rat model of LPS-induced ARDS avoided pulmonary function worsening and inhibited type I collagen deposition. In addition, hypertonic saline prevented pulmonary injury by decreasing metalloproteinase 9 (MMP-9) activity in tissue. Focal adhesion kinase (FAK) activation was reduced in HS group as well as neutrophil infiltration, NOS2 expression and NO content. Our study shows that fluid resuscitation with hypertonic saline decreases the progression of LPS-induced ARDS due to inhibition of pulmonary remodeling that is observed when regular saline is used.

Leptin and the control of pharyngeal patency during sleep in severe obesity.

RATIONALE: Obesity imposes mechanical loads on the upper airway, resulting in flow limitation and obstructive sleep apnea (OSA). In previous animal models, leptin has been considered to serve as a stimulant of ventilation and may prevent respiratory depression during sleep. We hypothesized that variations in leptin concentration among similarly obese individuals will predict differences in compensatory responses to upper airway obstruction during sleep. METHODS: An observational study was conducted in 23 obese women [body mass index (BMI): 46 ± 3 kg/m(2), age: 41 ± 12 yr] and 3 obese men (BMI: 46 ± 3 kg/m(2), age: 43 ± 4 yr). Subjects who were candidates for bariatric surgery were recruited to determine upper airway collapsibility under hypotonic conditions [pharyngeal critical pressure (passive PCRIT)], active neuromuscular responses to upper airway obstruction during sleep, and overnight fasting serum leptin levels. Compensatory responses were defined as the differences in peak inspiratory airflow (ΔVImax), inspired minute ventilation (ΔVI), and pharyngeal critical pressure (ΔPCRIT) between the active and passive conditions. RESULTS: Leptin concentration was not associated with sleep disordered breathing severity, passive PCRIT, or baseline ventilation. In the women, increases in serum leptin concentrations were significantly associated with increases in ΔVImax (r(2) = 0.44, P < 0.001), ΔVI (r(2) = 0.40, P < 0.001), and ΔPCRIT (r(2) = 0.19, P < 0.04). These responses were independent of BMI, waist-to-hip ratio, neck circumference, or sagittal girth. CONCLUSION: Leptin may augment neural compensatory mechanisms in response to upper airway obstruction, minimizing upper airway collapse, and/or mitigating potential OSA severity. Variability in leptin concentration among similarly obese individuals may contribute to differences in OSA susceptibility.

Efeito da exposição à fumaça de cigarro e ao resíduo de óleo diesel (ROFA) em pulmões de camundongos C57/BI6 / Effects of the exposure to cigarette smoke and residual oil fly ash (ROFA) in lungs of C57/Bl6 mice

Vários mecanismos que participam do desenvolvimento da DPOC (Doença Pulmonar Obstrutiva Crônica) não são ainda bem esclarecidos. Neste estudo, expusemos camundongos C57/Bl6, por 2 meses, à fumaça de cigarro e/ou à ROFA (resíduo de óleo diesel). Os animais expostos à fumaça de cigarro desenvolveram aumento da resistência de grandes vias aéreas, provavelmente por espessamento da sua parede, resultante de alterações nas células epiteliais. Estes animais também desenvolveram enfisema inicial, com distensão de espaços aéreos em algumas regiões pulmonares. Não houve recrutamento de células inflamatórias, alteração de fibras elásticas ou colágenas ou aumento do estresse oxidativo, medido pelo Isoprostano 8. Este trabalho sugere que há uma lesão pulmonar inicial que se caracteriza por alterações nas células epiteliais e algum grau de enfisema, que pode ser mediado pelas próprias células epiteliais.

Many of the mechanisms leading to CPOD (Chronic Pulmonary Obstructive Disease) are not completely understood. In the present study, we exposed C57/Bl6 mice, for two months, to cigarette smoke and/or ROFA (Residual Oil Fly Ash). Animals exposed to cigarette smoke had an increased in proximal airways resistance, probably due to the thickening of airways walls that followed changes in epithelial cells. These animals also had a small degree of emphysema, once air spaces enlargement could be noticed in circumscribed lung areas. We observed no inflammatory cells recruitment, elastic or collagen fibers deposition or increases in oxidative stress, measured by staining Isoprotane8. This study shows an early stage of the CPOD development, in which we can detect changes in epithelial cells and a small degree of emphysema, which could be mediated by these same epithelial cells.