PMID- 30628486 OWN - NLM STAT- MEDLINE DCOM- 20191230 LR - 20210109 IS - 1522-1504 (Electronic) IS - 1040-0605 (Print) IS - 1040-0605 (Linking) VI - 316 IP - 3 DP - 2019 Mar 1 TI - Small airway hyperresponsiveness in COPD: relationship between structure and function in lung slices. PG - L537-L546 LID - 10.1152/ajplung.00325.2018 [doi] AB - The direct relationship between pulmonary structural changes and airway hyperresponsiveness (AHR) in chronic obstructive pulmonary disease (COPD) is unclear. We investigated AHR in relation to airway and parenchymal structural changes in a guinea pig model of COPD and in COPD patients. Precision-cut lung slices (PCLS) were prepared from guinea pigs challenged with lipopolysaccharide or saline two times weekly for 12 wk. Peripheral PCLS were obtained from patients with mild to moderate COPD and non-COPD controls. AHR to methacholine was measured in large and small airways using video-assisted microscopy. Airway smooth muscle mass and alveolar airspace size were determined in the same slices. A mathematical model was used to identify potential changes in biomechanical properties underlying AHR. In guinea pigs, lipopolysaccharide increased the sensitivity of large (>150 mum) airways toward methacholine by 4.4-fold and the maximal constriction of small airways (<150 mum) by 1.5-fold. Similarly increased small airway responsiveness was found in COPD patients. In both lipopolysaccharide-challenged guinea pigs and patients, airway smooth muscle mass was unaltered, whereas increased alveolar airspace correlated with small airway hyperresponsiveness in guinea pigs. Fitting the parameters of the model indicated that COPD weakens matrix mechanical properties and enhances stiffness differences between the airway and the parenchyma, in both species. In conclusion, this study demonstrates small airway hyperresponsiveness in PCLS from COPD patients. These changes may be related to reduced parenchymal retraction forces and biomechanical changes in the airway wall. PCLS from lipopolysaccharide-exposed guinea pigs may be useful to study mechanisms of small airway hyperresponsiveness in COPD. FAU - Maarsingh, Harm AU - Maarsingh H AD - Department of Molecular Pharmacology, University of Groningen , Groningen , The Netherlands. AD - Department of Pharmaceutical Sciences, Lloyd L. Gregory School of Pharmacy, Palm Beach Atlantic University , West Palm Beach, Florida. AD - Groningen Research Institute of Asthma and Chronic Obstructive Pulmonary Disease, University Medical Center Groningen, University of Groningen , Groningen , The Netherlands. AD - Groningen Research Institute of Pharmacy, University of Groningen , Groningen , The Netherlands. FAU - Bidan, Cecile M AU - Bidan CM AD - Laboratoire Interdisciplinaire de Physique, Centre for Scientific Research, Universite Grenoble Alpes , Grenoble , France. AD - Department of Biomaterials, Max Planck Institute of Colloids and Interfaces , Potsdam , Germany. FAU - Brook, Bindi S AU - Brook BS AD - School of Mathematical Sciences, University of Nottingham , Nottingham , United Kingdom. FAU - Zuidhof, Annet B AU - Zuidhof AB AD - Department of Molecular Pharmacology, University of Groningen , Groningen , The Netherlands. AD - Groningen Research Institute of Asthma and Chronic Obstructive Pulmonary Disease, University Medical Center Groningen, University of Groningen , Groningen , The Netherlands. AD - Groningen Research Institute of Pharmacy, University of Groningen , Groningen , The Netherlands. FAU - Elzinga, Carolina R S AU - Elzinga CRS AD - Department of Molecular Pharmacology, University of Groningen , Groningen , The Netherlands. AD - Groningen Research Institute of Asthma and Chronic Obstructive Pulmonary Disease, University Medical Center Groningen, University of Groningen , Groningen , The Netherlands. AD - Groningen Research Institute of Pharmacy, University of Groningen , Groningen , The Netherlands. FAU - Smit, Marieke AU - Smit M AD - Department of Molecular Pharmacology, University of Groningen , Groningen , The Netherlands. AD - Department of Pathology and Medical Biology, University Medical Center Groningen , Groningen , The Netherlands. AD - Groningen Research Institute of Asthma and Chronic Obstructive Pulmonary Disease, University Medical Center Groningen, University of Groningen , Groningen , The Netherlands. FAU - Oldenburger, Anouk AU - Oldenburger A AD - Department of Molecular Pharmacology, University of Groningen , Groningen , The Netherlands. AD - Groningen Research Institute of Asthma and Chronic Obstructive Pulmonary Disease, University Medical Center Groningen, University of Groningen , Groningen , The Netherlands. AD - Groningen Research Institute of Pharmacy, University of Groningen , Groningen , The Netherlands. FAU - Gosens, Reinoud AU - Gosens R AD - Department of Molecular Pharmacology, University of Groningen , Groningen , The Netherlands. AD - Groningen Research Institute of Asthma and Chronic Obstructive Pulmonary Disease, University Medical Center Groningen, University of Groningen , Groningen , The Netherlands. AD - Groningen Research Institute of Pharmacy, University of Groningen , Groningen , The Netherlands. FAU - Timens, Wim AU - Timens W AD - Department of Pathology and Medical Biology, University Medical Center Groningen , Groningen , The Netherlands. AD - Groningen Research Institute of Asthma and Chronic Obstructive Pulmonary Disease, University Medical Center Groningen, University of Groningen , Groningen , The Netherlands. FAU - Meurs, Herman AU - Meurs H AD - Department of Molecular Pharmacology, University of Groningen , Groningen , The Netherlands. AD - Groningen Research Institute of Asthma and Chronic Obstructive Pulmonary Disease, University Medical Center Groningen, University of Groningen , Groningen , The Netherlands. AD - Groningen Research Institute of Pharmacy, University of Groningen , Groningen , The Netherlands. LA - eng GR - MR/M004643/1/MRC_/Medical Research Council/United Kingdom PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20190110 PL - United States TA - Am J Physiol Lung Cell Mol Physiol JT - American journal of physiology. Lung cellular and molecular physiology JID - 100901229 RN - 0 (Lipopolysaccharides) SB - IM MH - Adult MH - Aged MH - Airway Remodeling/*physiology MH - Animals MH - Asthma/pathology/physiopathology MH - Disease Models, Animal MH - Female MH - Guinea Pigs MH - Humans MH - Lipopolysaccharides/pharmacology MH - Lung/pathology/physiopathology MH - Male MH - Middle Aged MH - Muscle, Smooth/*drug effects/physiopathology MH - Pulmonary Disease, Chronic Obstructive/chemically induced/*pathology/*physiopathology MH - Respiratory Hypersensitivity/chemically induced/pathology/physiopathology PMC - PMC6459292 OTO - NOTNLM OT - airway constriction OT - airway remodeling OT - biomechanical modeling OT - emphysema OT - human lung COIS- Part of this study was supported by a grant from Novartis UK. EDAT- 2019/01/11 06:00 MHDA- 2019/12/31 06:00 PMCR- 2019/01/10 CRDT- 2019/01/11 06:00 PHST- 2019/01/11 06:00 [pubmed] PHST- 2019/12/31 06:00 [medline] PHST- 2019/01/11 06:00 [entrez] PHST- 2019/01/10 00:00 [pmc-release] AID - L-00325-2018 [pii] AID - 10.1152/ajplung.00325.2018 [doi] PST - ppublish SO - Am J Physiol Lung Cell Mol Physiol. 2019 Mar 1;316(3):L537-L546. doi: 10.1152/ajplung.00325.2018. Epub 2019 Jan 10.