ABSTRACT
OBJECTIVE: The aim was to create pathological changes in mice relevant to human smoke exposure that can be used to further understand the mechanisms and pathology of smoke-induced inflammatory disease. METHODS: Mice were exposed to tobacco smoke or lipopolysaccharide (LPS) to generate an inflammatory infiltrate within the lungs. RESULTS: Tobacco smoke exposure over a 4 day period led to neutrophilia in the lungs of BALB/c mice. Within the inflammatory exudates, significant changes were also seen in protein levels of IL-1B, IL-6, MIP-2, KC (IL-8) and TIMP-1 as measured by ELISA. Further protein changes, as measured via multiplex analysis revealed increased levels of MMP-9, MDC, LIF and MCP-1, amongst other mediators. Major changes in whole lung tissue gene expression patterns were observed. The neutrophilia seen after smoke exposure was steroid-insensitive, relative to doses of steroid needed to reduce LPS-driven neutrophilia in controls. This exposes pathological switches that are changed upon exposure to tobacco smoke, rendering steroids less effective under these conditions. Challenge of chemokine receptor type 1 (CCR1) KO mice in the tobacco smoke model showed that lack of this gene protected the mice from smoke-induced inflammation. CONCLUSIONS: This suggests the CCR1 receptor has a key role in the pathogenesis of smoke-induced inflammation.
Subject(s)
Inflammation/chemically induced , Nicotiana/adverse effects , Receptors, CCR1/metabolism , Smoke/adverse effects , Animals , Bronchoalveolar Lavage Fluid/chemistry , Female , Gene Expression , Humans , Inflammation/drug therapy , Inflammation/immunology , Lipopolysaccharides/immunology , Lipopolysaccharides/pharmacology , Mice , Mice, Inbred BALB C , Mice, Knockout , Receptors, CCR1/genetics , Steroids/therapeutic useABSTRACT
BACKGROUND: Matrix metalloproteases (MMPs) are believed to be important in the pathogenesis of cigarette smoke-induced emphysema, but this hypothesis has only been proved in the mouse and its applicability to other species, particularly humans, is uncertain. The role of MMPs in smoke-induced small airway remodelling is unknown. METHODS: The effects of a dual MMP-9/MMP-12 inhibitor, AZ11557272, on the development of anatomical and functional changes of chronic obstructive pulmonary disease (COPD) in guinea pigs exposed daily to cigarette smoke for up to 6 months were examined. RESULTS: At all times, smoke-induced increases in lavage inflammatory cells, lavage desmosine (a marker of elastin breakdown) and serum tumour necrosis factor alpha (TNFalpha) were completely abolished by AZ11557272. At 6 months there was an increase in lung volumes and airspace size. AZ11557272 returned the pressure- volume curve to control levels, decreased smoke-induced increases in total lung capacity, residual volume and vital capacity by about 70%, and also reversed smoke-induced airspace enlargement by about 70%. There was a very strong correlation between surface to volume ratio and both lavage desmosine and serum TNFalpha levels. AZ11557272 protected against smoke-mediated increases in small airway wall thickness but did not prevent smoke-induced increases in mean pulmonary artery pressure. CONCLUSIONS: An MMP-9/MMP-12 inhibitor can substantially ameliorate morphological emphysema, small airway remodelling and the functional consequences of these lesions in a non-murine species. These findings strengthen the idea that MMPs are important mediators of the anatomical changes behind COPD in humans, and suggest that MMP-9 and MMP-12 may be potential intervention targets.
