Abstract
BackgroundLung cancer often develops in association with chronic pulmonary inflammatory diseases with an influx of neutrophils. More detailed information on inflammatory pathways and the role of neutrophils herein is a prerequisite for understanding the mechanism of inflammation associated cancer.MethodsIn the present study, we used microarrays in order to obtain a global view of the transcriptional responses of the lung to LPS in mice, which mimics an acute lung inflammation. To investigate the influence of neutrophils in this process, we depleted mice from circulating neutrophils by treatment with anti-PMN antibodies prior to LPS exposure.ResultsA total of 514 genes was greater than 1.5-fold differentially expressed in the LPS induced lung inflammation model. 394 of the 514 were up regulated genes mostly involved in cell cycle and immune/inflammation related processes, such as cytokine/chemokine activity and signalling. Down regulated genes represented nonimmune processes, such as development, metabolism and transport. Notably, the number of genes and pathways that were differentially expressed, was reduced when animals were depleted from circulating neutrophils, confirming the central role of neutrophils in the inflammatory response. Furthermore, there was a significant correlation between the differentially expressed gene list and the promutagenic DNA lesion M1dG, suggesting that it is the extent of the immune response which drives genetic instability in the inflamed lung. Several genes that were specifically regulated by the presence of activated neutrophils could be identified and these were mostly involved in interferon signalling, oxidative stress response and cell cycle progression. The latter possibly refers to a higher rate of cell turnover in the inflamed lung with neutrophils, suggesting that the neutrophil influx is associated with a higher risk for the accumulation and fixation of mutations.ConclusionGene expression profiling identified specific genes and pathways that are related to neutrophilic inflammation and could be associated to cancer development and indicate an active role of neutrophils in mediating the LPS induced inflammatory response in the mouse lung.
Highlights
Lung cancer often develops in association with chronic pulmonary inflammatory diseases with an influx of neutrophils
It has been suggested that the accumulation of these neutrophils in the lumen of the lung is related to lung cancer risk [5], implying a significant role of the neutrophilic inflammation in the carcinogenic response [6]
We present the profiles of differentially expressed genes in lung tissue due to neutrophilic inflammation and investigated whether neutrophil induced genes are associated with induction of genotoxicity
Summary
Lung cancer often develops in association with chronic pulmonary inflammatory diseases with an influx of neutrophils. More detailed information on inflammatory pathways and the role of neutrophils is a prerequisite for understanding the mechanism of inflammation associated cancer. Inflammation is often considered to be a critical component of tumourigenesis, since many cancers arise at sites of infection, chronic irritation and inflammation [1,2]. Subjects suffering from inflammatory pulmonary diseases, such as chronic obstructive pulmonary disease (COPD)/emphysema, have an increased risk for developing lung cancer [3]. One common characteristic of many inflammatory lung disorders is the influx of polymorphonuclear neutrophils (PMN), which are highly specialised members of the innate immune system. During an invasion of pathogens, neutrophils are recruited to the site of inflammation and their life span is increased up to 4 days [4]. It has been suggested that the accumulation of these neutrophils in the lumen of the lung is related to lung cancer risk [5], implying a significant role of the neutrophilic inflammation in the carcinogenic response [6]
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