Lung recruitment and derecruitment contribute significantly to variations in the elastance of the respiratory system during mechanical ventilation. However, the decreases in elastance that occur with deep inflation are transient, especially in acute lung injury. Bates and Irvin (8) proposed a model of the lung that recreates time-varying changes in elastance as a result of progressive recruitment and derecruitment of lung units. The model is characterized by distributions of critical opening and closing pressures throughout the lung and by distributions of speeds with which the processes of opening and closing take place once the critical pressures have been achieved. In the present study, we adapted this model to represent a mechanically ventilated mouse. We fit the model to data collected in a previous study from control mice and mice in various stages of acid-induced acute lung injury (3). Excellent fits to the data were obtained when the normally distributed critical opening pressures were about 5 cmH(2)O above the closing pressures and when the hyperbolically distributed opening velocities were about an order of magnitude greater than the closing velocities. We also found that, compared with controls, the injured mice had markedly increased opening and closing pressures but no change in the velocities, suggesting that the key biophysical change wrought by acid injury is dysfunction of surface tension at the air-liquid interface. Our computational model of lung recruitment and derecruitment dynamics is thus capable of accurately mimicking data from mice with acute lung injury and may provide insight into the altered biophysics of the injured lung.

Nitrogen mustard (NM) is a toxic alkylating agent that causes damage to the respiratory tract. Evidence suggests that macrophages and inflammatory mediators including tumor necrosis factor (TNF)α contribute to pulmonary injury. Pentoxifylline is a TNFα inhibitor known to suppress inflammation. In these studies, we analyzed the ability of pentoxifylline to mitigate NM-induced lung injury and inflammation. Exposure of male Wistar rats (250 g; 8–10 weeks) to NM (0.125 mg/kg, i.t.) resulted in severe histolopathological changes in the lung within 3 d of exposure, along with increases in bronchoalveolar lavage (BAL) cell number and protein, indicating inflammation and alveolar-epithelial barrier dysfunction. This was associated with increases in oxidative stress proteins including lipocalin (Lcn)2 and heme oxygenase (HO)-1 in the lung, along with pro-inflammatory/cytotoxic (COX-2+ and MMP-9+), and anti-inflammatory/wound repair (CD163+ and Gal-3+) macrophages. Treatment of rats with pentoxifylline (46.7 mg/kg, i.p.) daily for 3 d beginning 15 min after NM significantly reduced NM-induced lung injury, inflammation, and oxidative stress, as measured histologically and by decreases in BAL cell and protein content, and levels of HO-1 and Lcn2. Macrophages expressing COX-2 and MMP-9 also decreased after pentoxifylline, while CD163+ and Gal-3+ macrophages increased. This was correlated with persistent upregulation of markers of wound repair including pro-surfactant protein-C and proliferating nuclear cell antigen by Type II cells. NM-induced lung injury and inflammation were associated with alterations in the elastic properties of the lung, however these were largely unaltered by pentoxifylline. These data suggest that pentoxifylline may be useful in treating acute lung injury, inflammation and oxidative stress induced by vesicants.

Surfactant protein-D (Sftpd) is a pulmonary collectin important in down-regulating macrophage inflammatory responses. In these experiments, we analyzed the effects of chronic macrophage inflammation attributable to loss of Sftpd on the persistence of ozoneinduced injury, macrophage activation, and altered functioning in the lung. Wild-type (Sftpd 1/1 ) and Sftpd 2/2 mice (aged 8 wk) were exposed to air or ozone (0.8 parts per million, 3 h). Bronchoalveolar lavage (BAL) fluid and tissue were collected 72 hours later. In Sftpd 2/2 mice, but not Sftpd 1/1 mice, increased BAL protein and nitrogen oxides were observed after ozone inhalation, indicating prolonged lung injury and oxidative stress. Increased numbers of macrophages were also present in BAL fluid and in histologic sections from Sftpd 2/2 mice. These cells were enlarged and foamy, suggesting that they were activated. This conclusion was supported by findings of increased BAL chemotactic activity, and increased expression of inducible nitric oxide synthase in lung macrophages. In both Sftpd 1/1 and Sftpd 2/2 mice, inhalation of ozone was associated with functional alterations in the lung. Although these alterations were limited to central airway mechanics in Sftpd 1/1 mice, both central airway and parenchymal mechanics were modified by ozone exposure in Sftpd 2/2 mice. The most notable changes were evident in resistance and elastance spectra and baseline lung function, and in lung responsiveness to changes in positive endexpiratory pressure. These data demonstrate that a loss of Sftpd is associated with prolonged lung injury, oxidative stress, and macrophage accumulation and activation in response to ozone, and with more extensive functional changes consistent with the loss of parenchymal integrity. Keywords: ozone; surfactant protein-D; macrophages; iNOS; lung functionOzone is a ubiquitous urban air pollutant generated as a component of photochemical smog. Inhaled ozone causes ozonation and the peroxidation of proteins and lipids in the epithelial lining fluid layer of the lung, resulting in the production of oxidized proteins, aldehydes, and free radicals, which can damage surrounding tissue (1, 2). This is accompanied by an accumulation of activated macrophages in the lung and the production of additional cytotoxic and proinflammatory mediators, including reactive oxygen and reactive nitrogen species (ROS and RNS, respectively) that contribute to tissue injury (3). Airway and tissue mechanics are also altered after ozone exposure. Thus, in humans, ozone inhalation leads to a deterioration of pulmonary function, as measured by decreases in respiratory frequency, forced expiratory volume in 1 second, and forced vital capacity, and increases in airway resistance (1,4,5). Ozone has been shown to exacerbate asthma and increase airway hyperreactivity (5, 6), and to contribute to increased morbidity and mortality in patients with chronic obstructive pulmonary disease (COPD) (7,8). Similar alterations in lung function and increases in sensitivity to ozone have b...

Heterogeneity of regional lung mechanics is an important determinant of the work of breathing and may be a risk factor for ventilator associated lung injury. The ability to accurately assess heterogeneity may have important implications for monitoring disease progression and optimizing ventilator settings. Inverse modeling approaches, when applied to dynamic pulmonary impedance data (Z(L)), are thought to be sensitive to the detection of mechanical heterogeneity with the ability to characterize global lung function using a minimal number of free parameters. However, the reliability and bias associated with such model-based estimates of heterogeneity are unknown. We simulated Z(L) spectra from healthy, emphysematous, and acutely injured lungs using a computer-generated anatomic canine structure with asymmetric Horsfield branching and various predefined distributions of stochastic lung tissue heterogeneity. Various inverse models with distinct topologies incorporating linear resistive and inertial airways with parallel tissue viscoelasticity were then fitted to these Z(L) spectra and evaluated in terms of their quality of fit as well as the accuracy and reliability of their respective model parameters. While all model topologies detected appropriate changes in tissue heterogeneity, only a topology consisting of lumped airway properties with distributed tissue properties yielded accurate estimates of both mean lung tissue stiffness and the spread of regional elastances. These data demonstrate that inverse modeling approaches applied to noninvasive measures of Z(L) may provide reliable and accurate assessments of lung tissue heterogeneity as well as insight into distributed lung mechanical properties.

Groves AM, Gow AJ, Massa CB, Hall L, Laskin JD, Laskin DL. Age-related increases in ozone-induced injury and altered pulmonary mechanics in mice with progressive lung inflammation.