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Acute Lung Injury and Pulmonary Vascular Permeability: Use of Transgenic Models

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Abstract

Acute lung injury is a general term that describes injurious conditions that can range from mild interstitial edema to massive inflammatory tissue destruction. This review will cover theoretical considerations and quantitative and semi‐quantitative methods for assessing edema formation and increased vascular permeability during lung injury. Pulmonary edema can be quantitated directly using gravimetric methods, or indirectly by descriptive microscopy, quantitative morphometric microscopy, altered lung mechanics, high‐resolution computed tomography, magnetic resonance imaging, positron emission tomography, or x‐ray films. Lung vascular permeability to fluid can be evaluated by measuring the filtration coefficient (Kf) and permeability to solutes evaluated from their blood to lung clearances. Albumin clearances can then be used to calculate specific permeability‐surface area products (PS) and reflection coefficients (σ). These methods as applied to a wide variety of transgenic mice subjected to acute lung injury by hyperoxic exposure, sepsis, ischemia‐reperfusion, acid aspiration, oleic acid infusion, repeated lung lavage, and bleomycin are reviewed. These commonly used animal models simulate features of the acute respiratory distress syndrome, and the preparation of genetically modified mice and their use for defining specific pathways in these disease models are outlined. Although the initiating events differ widely, many of the subsequent inflammatory processes causing lung injury and increased vascular permeability are surprisingly similar for many etiologies. © 2011 American Physiological Society. Compr Physiol 1:835‐882, 2011.

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Figure 1. Figure 1.

Relationship between protein clearance and filtration rate for albumin across a simple homoporous membrane as PS is increased from 0 to 0.08 at a constant value of σ = 0.9. Reproduced with permission and modified from Rippe and Haraldsson .

Figure 2. Figure 2.

Light micrographs of (A) uninjured mouse lungs and (B) edematous mouse lungs injured by high airway pressure ventilation. Perivascular edema cuffs and alveolar flooding are shown. Br = bronchus; PA = lobar pulmonary artery; V = pulmonary vein.

Figure 3. Figure 3.

Morphometry estimates of the perivascular edema cuff and alveolar fluid volume fractions in rat lungs injured by thapsigargin (Solid bars) or 14,15‐epoxyeicosanoic acid (14,15‐EET). Mean values of volume fractions indicate vascular segment‐specific permeability effects of the agonists. Data replotted from Alvarez et al. .

Figure 4. Figure 4.

Static pressure‐volume curve of rat lungs before and after injury by high peak inflation pressure (PIP) ventilation showing the increased pressures of the lower inflection point (LIP) and upper inflection point (UIP). Reproduced with permission from Imanaka et al. .

Figure 5. Figure 5.

The change in static lung compliance as a function of the change in lung wet‐to‐dry weight ratios in wild‐type and PLA2 knockout mice treated with either intratracheal lipopolysaccharide (LPS) or saline, or LPS + anti‐PLA2 antibodies. Data replotted from Munoz et al. .

Figure 6. Figure 6.

Relationship of lung mechanical parameters as a function of lung weight during edema formation in mice after 60‐h exposure to hyperoxia. Tissue damping (G) and elastance (H) calculated from the constant‐phase model and the tissue resistance (Rti) are shown. Raw is airway resistance. Data replotted from Petak et al. .

Figure 7. Figure 7.

Comparison of extravascular lung water determine from magnetic resonance density with gravimetric measurements. Reproduced with permission from Cutillo et al. .

Figure 8. Figure 8.

Graded clearances between plasma and BAL fluid related to the degree of injury. Reproduced with permission from Yoshikawa et al. .

Figure 9. Figure 9.

Clearance of radiolabeled albumin into tissue (QA,t), or pulmonary lymph (QA,l), and their sum (QA,s) as a function of capillary filtration pressure in intact dogs. Reproduced with permission from Ishibashi et al. .

Figure 10. Figure 10.

Allometric relationship of total lung filtration coefficient (Kf,t), alveolar surface area (SALV), pulmonary capillary surface area (SCAP), and pulmonary diffusion coefficient (DLO2) for oxygen to body mass of several species. Reproduced with permission from Parker and Townsley

Figure 11. Figure 11.

Comparison of filtration rates in dog lung lobes calculated from laser densitometry changes in hematocrit concentration and gravimetric weight gain as a function of time after an increase in pulmonary capillary pressure. Reproduced with permission from Parker et al. * p < 0.05 vs. laser method.

Figure 12. Figure 12.

The relationship between the microvascular/total vascular compliance ratio and filtration coefficient in oleic acid injured dog lungs after an increases in either pulmonary vascular blood flow or pressure. *P <0.05. Data replotted from Anglade et al. .

Figure 13. Figure 13.

Pathways for production of reactive oxygen and nitrogen species. l‐Arg. = l‐arginine; SOD = superoxide dismutase; and R‐SNO = nitrosylated residues, that is, tyrosine and cysteine.

Figure 14. Figure 14.

Diagram of the cellular components and pathways implicated in increased lung vascular permeability during hyperoxia. MMP = metalloproteinase; ROS = reactive oxygen species; PMN = polymorphonuclear neutrophil; IFN = interferon; and NOS = nitric oxide synthase.

Figure 15. Figure 15.

Pathways activated by lipopolysaccharide (LPS) for induction of lung injury. LPB = LPS‐binding protein; SFK = Src family kinases; MyD88 = myeloid differentiation primary response protein 88; TIRAP = toll‐interleukin 1 receptor domain‐containing adaptor protein; PI3K = phosphoinositide 3‐kinases; PMN = polymorphonuclear neutrophil; TF = tissue factor; TLR4 = toll‐like receptor 4; VII and X = clotting factors; ROS = reactive oxygen species; and RNS = reactive nitrogen species.

Figure 16. Figure 16.

Diagram of the cellular components and pathways implicated in increased lung vascular permeability after ischemia‐reperfusion. MMP = metalloproteinase; ROS = reactive oxygen species; PMN = polymorphonuclear neutrophil; IFN = interferon; and NOS = nitric oxide synthase.

Figure 17. Figure 17.

Diagram of the cellular components and pathways implicated in increased lung vascular permeability associated with ventilator‐induced lung injury. MMP = metalloproteinase; ROS = reactive oxygen species; PMN = polymorphonuclear neutrophil; IFN = interferon; and NOS = nitric oxide synthase.



Figure 1.

Relationship between protein clearance and filtration rate for albumin across a simple homoporous membrane as PS is increased from 0 to 0.08 at a constant value of σ = 0.9. Reproduced with permission and modified from Rippe and Haraldsson .



Figure 2.

Light micrographs of (A) uninjured mouse lungs and (B) edematous mouse lungs injured by high airway pressure ventilation. Perivascular edema cuffs and alveolar flooding are shown. Br = bronchus; PA = lobar pulmonary artery; V = pulmonary vein.



Figure 3.

Morphometry estimates of the perivascular edema cuff and alveolar fluid volume fractions in rat lungs injured by thapsigargin (Solid bars) or 14,15‐epoxyeicosanoic acid (14,15‐EET). Mean values of volume fractions indicate vascular segment‐specific permeability effects of the agonists. Data replotted from Alvarez et al. .



Figure 4.

Static pressure‐volume curve of rat lungs before and after injury by high peak inflation pressure (PIP) ventilation showing the increased pressures of the lower inflection point (LIP) and upper inflection point (UIP). Reproduced with permission from Imanaka et al. .



Figure 5.

The change in static lung compliance as a function of the change in lung wet‐to‐dry weight ratios in wild‐type and PLA2 knockout mice treated with either intratracheal lipopolysaccharide (LPS) or saline, or LPS + anti‐PLA2 antibodies. Data replotted from Munoz et al. .



Figure 6.

Relationship of lung mechanical parameters as a function of lung weight during edema formation in mice after 60‐h exposure to hyperoxia. Tissue damping (G) and elastance (H) calculated from the constant‐phase model and the tissue resistance (Rti) are shown. Raw is airway resistance. Data replotted from Petak et al. .



Figure 7.

Comparison of extravascular lung water determine from magnetic resonance density with gravimetric measurements. Reproduced with permission from Cutillo et al. .



Figure 8.

Graded clearances between plasma and BAL fluid related to the degree of injury. Reproduced with permission from Yoshikawa et al. .



Figure 9.

Clearance of radiolabeled albumin into tissue (QA,t), or pulmonary lymph (QA,l), and their sum (QA,s) as a function of capillary filtration pressure in intact dogs. Reproduced with permission from Ishibashi et al. .



Figure 10.

Allometric relationship of total lung filtration coefficient (Kf,t), alveolar surface area (SALV), pulmonary capillary surface area (SCAP), and pulmonary diffusion coefficient (DLO2) for oxygen to body mass of several species. Reproduced with permission from Parker and Townsley



Figure 11.

Comparison of filtration rates in dog lung lobes calculated from laser densitometry changes in hematocrit concentration and gravimetric weight gain as a function of time after an increase in pulmonary capillary pressure. Reproduced with permission from Parker et al. * p < 0.05 vs. laser method.



Figure 12.

The relationship between the microvascular/total vascular compliance ratio and filtration coefficient in oleic acid injured dog lungs after an increases in either pulmonary vascular blood flow or pressure. *P <0.05. Data replotted from Anglade et al. .



Figure 13.

Pathways for production of reactive oxygen and nitrogen species. l‐Arg. = l‐arginine; SOD = superoxide dismutase; and R‐SNO = nitrosylated residues, that is, tyrosine and cysteine.



Figure 14.

Diagram of the cellular components and pathways implicated in increased lung vascular permeability during hyperoxia. MMP = metalloproteinase; ROS = reactive oxygen species; PMN = polymorphonuclear neutrophil; IFN = interferon; and NOS = nitric oxide synthase.



Figure 15.

Pathways activated by lipopolysaccharide (LPS) for induction of lung injury. LPB = LPS‐binding protein; SFK = Src family kinases; MyD88 = myeloid differentiation primary response protein 88; TIRAP = toll‐interleukin 1 receptor domain‐containing adaptor protein; PI3K = phosphoinositide 3‐kinases; PMN = polymorphonuclear neutrophil; TF = tissue factor; TLR4 = toll‐like receptor 4; VII and X = clotting factors; ROS = reactive oxygen species; and RNS = reactive nitrogen species.



Figure 16.

Diagram of the cellular components and pathways implicated in increased lung vascular permeability after ischemia‐reperfusion. MMP = metalloproteinase; ROS = reactive oxygen species; PMN = polymorphonuclear neutrophil; IFN = interferon; and NOS = nitric oxide synthase.



Figure 17.

Diagram of the cellular components and pathways implicated in increased lung vascular permeability associated with ventilator‐induced lung injury. MMP = metalloproteinase; ROS = reactive oxygen species; PMN = polymorphonuclear neutrophil; IFN = interferon; and NOS = nitric oxide synthase.

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James C. Parker. Acute Lung Injury and Pulmonary Vascular Permeability: Use of Transgenic Models. Compr Physiol 2011, 1: 835-882. doi: 10.1002/cphy.c100013