Mechanical ventilation is an important tool in the management of respiratory failure. However, the ventilation strategy can initiate or exacerbate lung injury. Several mechanisms have been implicated in ventilator-induced lung injury (VILI), particularly cyclical airway collapse and reopening. Inferential data supports cyclical airway collapse as an important factor in the genesis of VILI, but it has never been definitively documented. Strategies minimizing alveolar over distension and cyclical airway closure decrease mortality in ARDS patients but are confounded by hypercapnic acidosis, itself a potential modulator of lung injury. Establishing the presence of cyclical airway collapse, its abolition with palliative interventions, and correlation with severity and distribution of injury is vital to understanding VILI and developing relevant strategies to prevent it. This proposal will evaluate mechanisms by which mechanical ventilation induces lung injury and initiates inflammation in a rabbit model of VILI caused solely by mechanical forces. I will address the following questions: 1) Is cyclical airway collapse and reopening a stimulus for inflammation? 2) Where in the lung and on which cell types do mechanical forces exert their effects? 3) Can we definitively document cyclical airway closure? 4) If so, can we accurately predict ventilatory conditions that prevent it? 5) Do non- mechanical forces (hypercapnia) play a protective role in VILI? Methods: Spatial inflammation distribution measured with monoclonal antibody ELISA and immunohistochemistry. Spatial injury measured by extravascular albumin accumulation and gravimetrics. Regional V and Q measured with aerosolized and perfused fluorescent microspheres. Global gas exchange measured with the multiple inert gas elimination technique. Ventilation heterogeneity measured with multiple breath nitrogen washout.
Aim 1 A: Examine how posture change and PEEP effect severity and distribution of injury and inflammation.
Aim 1 B: Determine the anatomical location and cell type(s) responsible inflammation in VILI.
Aim 2 A : Measure effects of hypercapnia on lung injury and inflammation during VILI.
Aim 2 B: Examine how hypercapnia alters hypoxic pulmonary vasoconstriction and reduces VILI.
Aim 2 C : Examine how hypercapnia effects ventilation heterogeneity and reduces VILI.
Aim 3 A: Document cyclical airway collapse and reopening via changes in regional ventilation distribution.
Aim 3 B: Validate a method to estimate appropriate PEEP level to prevent cyclical airway collapse.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
1K08HL004479-01A1
Application #
6359316
Study Section
Special Emphasis Panel (ZHL1-CSR-M (M1))
Program Officer
Colombini-Hatch, Sandra
Project Start
2001-07-01
Project End
2006-05-31
Budget Start
2001-07-01
Budget End
2002-05-31
Support Year
1
Fiscal Year
2001
Total Cost
$128,493
Indirect Cost
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
Sinclair, Scott E; Polissar, Nayak L; Altemeier, William A (2010) Spatial distribution of sequential ventilation during mechanical ventilation of the uninjured lung: an argument for cyclical airway collapse and expansion. BMC Pulm Med 10:25
Sinclair, Scott E; Chi, Emil; Lin, Hen-I et al. (2009) Positive end-expiratory pressure alters the severity and spatial heterogeneity of ventilator-induced lung injury: an argument for cyclical airway collapse. J Crit Care 24:206-11
Sinclair, Scott E; Molthen, Robert C; Haworth, Steve T et al. (2007) Airway strain during mechanical ventilation in an intact animal model. Am J Respir Crit Care Med 176:786-94
Altemeier, William A; Sinclair, Scott E (2007) Hyperoxia in the intensive care unit: why more is not always better. Curr Opin Crit Care 13:73-8
Desai, Leena P; Sinclair, Scott E; Chapman, Kenneth E et al. (2007) High tidal volume mechanical ventilation with hyperoxia alters alveolar type II cell adhesion. Am J Physiol Lung Cell Mol Physiol 293:L769-78
Sinclair, Scott E; Kregenow, David A; Starr, Ian et al. (2006) Therapeutic hypercapnia and ventilation-perfusion matching in acute lung injury: low minute ventilation vs inspired CO2. Chest 130:85-92
Chapman, Kenneth E; Sinclair, Scott E; Zhuang, Daming et al. (2005) Cyclic mechanical strain increases reactive oxygen species production in pulmonary epithelial cells. Am J Physiol Lung Cell Mol Physiol 289:L834-41
Sinclair, Scott E; Altemeier, William A; Matute-Bello, Gustavo et al. (2004) Augmented lung injury due to interaction between hyperoxia and mechanical ventilation. Crit Care Med 32:2496-501
Sinclair, Scott E; Kregenow, David A; Lamm, Wayne J E et al. (2002) Hypercapnic acidosis is protective in an in vivo model of ventilator-induced lung injury. Am J Respir Crit Care Med 166:403-8