Microarray analysis of regional cellular responses to local mechanical stress in acute lung injury

Abstract

-Human acute lung injury is characterized by heterogeneous tissue involvement, leading to the potential for extremes of mechanical stress and tissue injury when mechanical ventilation, required to support critically ill patients, is employed. Our goal was to establish whether regional cellular responses to these disparate local mechanical conditions could be determined as a novel approach toward understanding the mechanism of development of ventilator-associated lung injury. We utilized cross-species genomic microarrays in a unilateral model of ventilator-associated lung injury in anesthetized dogs to assess regional cellular responses to local mechanical conditions that potentially contribute pathogenic mechanisms of injury. Highly significant regional differences in gene expression were observed between lung apex/base regions as well as between gravitationally dependent/nondependent regions of the base, with 367 and 1,544 genes differentially regulated between these regions, respectively. Major functional groupings of differentially regulated genes included inflammation and immune responses, cell proliferation, adhesion, signaling, and apoptosis. Expression of genes encoding both acute lung injury-associated inflammatory cytokines and protective acute response genes were markedly different in the nondependent compared with the dependent regions of the lung base. We conclude that there are significant differences in the local responses to stress within the lung, and consequently, insights into the cellular responses that contribute to ventilator-associated lung injury development must be sought in the context of the mechanical heterogeneity that characterizes this syndrome. adult respiratory distress syndrome; mechanical ventilation; canine; computed tomography; cross-species microarray IN RECENT YEARS, THE FOCUS of research into acute lung injury (ALI) has shifted from primarily mechanical and supportive management towards investigation into the cellular and molecular basis of the disease process. However, despite a great deal of data suggesting interactions between mechanical stress, inflammation, and the development of lung injury, the pathogenesis of ventilator-associated lung injury (VALI) is not well understood. A hallmark of human ALI that is not captured in many small animal models is the marked heterogeneity of tissue involvement (19). Mechanical and biological phenomena potentially contributing to VALI vary widely throughout the lung and may be highly dependent on particular supportive interventions. Recognizing this, management strategies have implicitly sought to reduce this heterogeneity so as to minimize the presumed "injurious" mechanical events (such as overdistension or air space opening/closing) while maintaining adequate gas exchange for life support (21).We believe that VALI does in fact have its origin in inflammatory and other cellular responses in lung tissue exposed to (and possibly, predisposed to injury from) mechanical stress and hypothesize that these responses will vary throughout t...

Tubulin Acetylation and Histone Deacetylase 6 Activity in the Lung under Cyclic Load

“…Although the animals remain viable after ventilation at 80% TLC or higher, we have observed that prolonged ventilation (e.g., > 2 h) at higher volumes (80-100% TLC) results in hemorrhage and damage of the lung epithelium (data not shown), as has previously been shown by a number of labs (40)(41)(42)(43). However, at lower volumes, even for these extended periods of time, no damage was seen.…”

The Local and Systemic Inflammatory Transcriptome after Acute Kidney Injury

“…7 Identified SD for control kidney ( ϭ 0.274) and lung ( ϭ 0.271) tissues were submitted to the microarray sample size identifying formula 40 with power (1 Ϫ ␤) ϭ 90% and 1% FDR (significance level ␣ ϭ 0.01) for kidney and 2% for more heterogeneous lung tissue. 41 The power.t.test function of R2.3.1 program (www.r-project.org) identified fold change for kidney log 2 (⌬) ϭ 1.513 (numerical 2.85) and lung log 2 (⌬) ϭ 1.249 (numerical 2.38).…”

Role of the pulmonary epithelium and inflammatory signals in acute lung injury

“…Alternatively, a separate internal or mitochondrial pathway can mediate apoptosis via cytochrome c and caspase activation. Lung tissue from both humans with ALI and animal models of ALI demonstrate activation of apoptotic pathways in the alveolar epithelium [22,23]. Matute-Bello and colleagues reported that bronchoalveolar fluid from patients with ALI contained soluble Fas ligand (sFasL), and the concentration of sFasL at the onset of ARDS was significantly higher in patients who died [24].…”