ABSTRACT
Mechanical ventilation is the major cause of iatrogenic lung damage in intensive care units. Although inflammation is known to be involved in ventilator-induced lung injury (VILI), several aspects of this process are still unknown. Pentraxin 3 (PTX3) is an acute phase protein with important regulatory functions in inflammation which has been found elevated in patients with acute respiratory distress syndrome. This study aimed at investigating the direct effect of PTX3 production in the pathogenesis of VILI. Genetically modified mice deficient and that over express murine Ptx3 gene were subjected to high tidal volume ventilation (V(T)=45 mL/kg, PEEP(zero)). Morphological changes and time required for 50% increase in respiratory system elastance were evaluated. Gene expression profile in the lungs was also investigated in earlier times in Ptx3-overexpressing mice. Ptx3 knockout and wild-type mice developed same lung injury degree in similar times (156±42 min and 148±41 min, respectively; p=0.8173). However, Ptx3 over-expression led to a faster development of VILI in Ptx3-overexpressing mice (77±29 min vs 118±41 min, p=0.0225) which also displayed a faster kinetics of Il1b expression and elevated Ptx3, Cxcl1 and Ccl2 transcripts levels in comparison with wild-type mice assessed by quantitative real-time polymerase chain reaction. Ptx3 deficiency did not impacted the time for VILI induced by high tidal volume ventilation but Ptx3-overexpression increased inflammatory response and reflected in a faster VILI development.
Subject(s)
C-Reactive Protein/metabolism , Lung/metabolism , Respiration, Artificial/adverse effects , Serum Amyloid P-Component/metabolism , Ventilator-Induced Lung Injury/metabolism , Animals , C-Reactive Protein/genetics , Chemokine CCL2/biosynthesis , Chemokine CCL2/genetics , Chemokine CXCL1/biosynthesis , Chemokine CXCL1/genetics , Disease Models, Animal , Gene Expression Profiling , Inflammation/immunology , Inflammation/pathology , Lung/pathology , Lung/physiopathology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Serum Amyloid P-Component/genetics , Tidal Volume , Ventilator-Induced Lung Injury/pathology , Ventilator-Induced Lung Injury/physiopathology , Ventilators, Mechanical/adverse effectsABSTRACT
OBJECTIVE: To assess alcohol dehydrogenase 3 (ADH3) polymorphism at position Ile349Val as indicator of risk factor for upper aerodigestive tract (UADT) cancer to verify its association with UADT cancer in nonalcoholic or nonsmoking individuals. DESIGN: Cross-sectional study. SETTING: Primary care or referral center. PATIENTS: The study group consisted of 141 consecutive patients with newly diagnosed squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx admitted for surgical treatment. The comparison group consisted of 94 inpatients without cancer from the A. C. Camargo or other São Paulo (Brazil) hospital and 40 healthy individuals. INTERVENTION: All participants were interviewed and data were collected using a structured questionnaire. After written informed consent was obtained, 20 mL of blood was collected in heparinized tubes. MAIN OUTCOME MEASURES: Odds ratio for ADH3 genotypes using logistic regression models. RESULTS: After adjustment for sex, age, tobacco use, and history of cancer in first-degree family relatives, a significantly higher odds ratio for UADT cancer was observed among individuals with AA genotype and low cumulative alcohol consumption (< or =100 kg of ethanol) (odds ratio = 3.8 [95% confidence interval, 1.5-9.7]). A 4-fold increase in odds ratio for UADT cancer among individuals with AA genotype and low tobacco consumption (< or =25 pack-years) was also found in the adjusted model. CONCLUSIONS: These results suggest that genotype AA may be a risk factor for UADT cancer, especially in individuals with low alcohol or tobacco consumption. However, further epidemiological case-control or cohort studies, preferably prospective, are needed to establish the exact role of ADH3 polymorphism and its association with the development of UADT cancers.
