title: Nontypeable Haemophilus influenzae-Promoted Proliferation of Kras-Induced Early Adenomatous Lesions Is Completely Dependent on Toll-Like Receptor Signaling.
abstract: Chronic obstructive pulmonary disease (COPD) is a risk factor for lung cancer. COPD is characterized by chronic airway inflammation and lung infections. The airways of patients with COPD are frequently colonized with bacteria [eg, nontypeable Haemophilus influenzae (NTHi)] that cause pulmonary inflammation and exacerbations. Pulmonary adenocarcinomas are frequently associated with an activating mutation in the KRAS gene. We determined the function of Toll-like receptor (TLR) signaling on the progression of Kras-induced early adenomatous lesions in the lung. Wild-type (WT) mice and mice doubly deficient in Tlr-2 and -4 (Tlr2/4-/-), both with an oncogenic Kras allele in lung epithelium, were exposed to NTHi for 4 weeks. Exposure to NTHi resulted in increased tumor proliferation and growth in WT mice, but not in Tlr2/4-/-mice. Alveolar adenomatous hyperplasia and adenocarcinoma were significantly increased in WT mice compared with Tlr2/4-/-mice. The average size of tumors was significantly larger in WT mice, whereas there was no difference in the number of alveolar lesions between WT and Tlr2/4-/-mice. NTHi-induced pulmonary neutrophilic inflammation and tumor-associated neutrophils were reduced in Tlr2/4-/-mice. Thus, subsequent to a driver mutation, NTHi-induced inflammation promotes proliferation of early adenomatous lesions in a TLR-dependent manner.
authors.affiliation: Department of Internal Medicine V-Pulmonology, Allergology and Respiratory Critical Care Medicine, Saarland University, Homburg/Saar, Germany.
authors.forename: Christopher
authors.initials: C
authors.lastname: Jungnickel
authors.affiliation: Department of Pathology, Saarland University, Homburg/Saar, Germany.
authors.forename: Philipp A
authors.initials: PA
authors.lastname: Schnabel
authors.affiliation: Department of Pathology, Saarland University, Homburg/Saar, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Bohle
authors.affiliation: Department of Medicine A-Hematology, Oncology and Pulmonology, University Hospital Münster, Münster, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Wiewrodt
authors.affiliation: Department of Internal Medicine V-Pulmonology, Allergology and Respiratory Critical Care Medicine, Saarland University, Homburg/Saar, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Herr
authors.affiliation: Department of Internal Medicine V-Pulmonology, Allergology and Respiratory Critical Care Medicine, Saarland University, Homburg/Saar, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Bals
authors.affiliation: Department of Internal Medicine V-Pulmonology, Allergology and Respiratory Critical Care Medicine, Saarland University, Homburg/Saar, Germany. Electronic address: christoph.beisswenger@uks.eu.
authors.forename: Christoph
authors.initials: C
authors.lastname: Beisswenger
mesh_terms: D000230:Adenocarcinoma / Q000503:physiopathology; D000818:Animals; D049109:Cell Proliferation / Q000502:physiology; D011905:Genes, ras / Q000502:physiology*; D006192:Haemophilus Infections / Q000503:physiopathology; D006193:Haemophilus influenzae / Q000502:physiology; D008175:Lung Neoplasms / Q000503:physiopathology; D051379:Mice; D009504:Neutrophils / Q000502:physiology; D029424:Pulmonary Disease, Chronic Obstructive / Q000503:physiopathology* / Q000821:virology; D015398:Signal Transduction / Q000502:physiology; D051195:Toll-Like Receptor 2 / Q000172:deficiency / Q000502:physiology*; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000502:physiology*; D018631:ras Proteins / Q000378:metabolism
chemical_list: D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D018631:ras Proteins