Dhaliwal, Kanwaldeep

Medical Research Council (MRC)

2013-11-08T16:00:47Z

2013-11-08T16:00:47Z

2013-07-06

BACKGROUND: Acute lung injury (ALI) and nosocomial pneumonia are major causes of morbidity and mortality. There are 200,000 cases per year of ALI in the US with a mortality of 40%. On the intensive care unit (ICU), ALI accounts for over 40% of all ventilated patients at any one time. Despite this huge burden on healthcare and the relatively high prevalence, no therapies currently exist in clinical practice that attenuate the condition. The pathophysiology and aetiology of ALI is multifactorial but neutrophilic influx and consequent damage to the endothelial-epithelial interface are regarded as central features. Alongside neutrophils, peripheral blood monocytes (PBMs) are recruited to the acutely inflamed lung. The role played by PBMs in perpetuating the pathogenic neutrophilic influx remains poorly characterised. Nosocomial pneumonia is also a major problem with drug resistant organisms. With the increasing prevalence of antibiotic resistance and the paucity of novel antimicrobials being generated by pharmaceutical companies, there is real concern that the end of the ‘antibiotic era’ may be approaching. AIMS: 1) To develop murine models of lung inflammation and infection 2) To establish the role of the PBM in perpetuating the neutrophilic response in ALI 3) To develop non-invasive methodologies to study the trafficking of cells and molecular events within the inflamed lung 4) To apply a novel antimicrobial to prevent and treat nosocomial pneumonia. METHODS: A murine model of ALI was utilised using direct intratracheal instillation of lipopolysaccharide. To this model 3 different PBM depletion strategies were applied to study the effect on neutrophil recruitment and consequent lung injury. Non invasive optical imaging was utilised to study the effect of PBM depletion on proteolytic events within the murine lung. To understand cellular trafficking, cell labeling strategies were compared for primary murine macrophages with whole body optical imaging in mice. Murine models of Staphylococcus aureus, Pseudomonas aeruginosa and Burkholderia cepacia were established and a novel antimicrobial agent called the nonalysine like peptoid (NLLP) tested in vitro and in vivo for efficacy. RESULTS: PBM depletion significantly attenuated neutrophil recruitment in an established model of ALI. Near infrared (NIR) optical imaging permitted the non invasive tracking of primary murine cells. A non toxic peptidomimetic agent (NLLP) possessed antimicrobial activity against gram positive and gram negative pathogens with therapeutic and prophylactic efficacy in vivo. CONCLUSIONS: PBM depletion is a potential therapeutic strategy for treating ALI. Further studies are required to determine the exact mechanism by which PBMs orchestrate neutrophil recruitment. Optical imaging is a versatile platform for molecular imaging. A novel antimicrobial agent termed NLLP has been discovered with therapeutic and prophylactic efficacy against multi-drug resistant pathogens.

http://hdl.handle.net/1842/8100

en

The University of Edinburgh

Monocytes Control Second-Phase Neutrophil Emigration in Established Lipopolysaccharide-induced Murine Lung Injury. Dhaliwal K, Scholefield E, Ferenbach D, Gibbons M, Duffin R, Dorward DA, Morris AC, Humphries D, Mackinnon A, Wilkinson TS, Wallace WA, van Rooijen N, Mack M, Rossi AG, Davidson DJ, Hirani N, Hughes J, Haslett C, Simpson AJ. Am J Respir Crit Care Med. 2012 Sep 15;186(6):514-24.

In vivo mononuclear cell tracking using superparamagnetic particles of iron oxide: feasibility and safety in humans.Richards JM, Shaw CA, Lang NN, Williams MC, Semple SI, MacGillivray TJ, Gray C, Crawford JH, Alam SR, Atkinson AP, Forrest EK, Bienek C, Mills NL, Burdess A, Dhaliwal K, Simpson AJ, Wallace WA, Hill AT, Roddie PH, McKillop G, Connolly TA, Feuerstein GZ, Barclay GR, Turner ML, Newby DE. Circ Cardiovasc Imaging. 2012 Jul;5(4):509-17.

Macrophage/monocyte depletion by clodronate, but not diphtheria toxin, improves renal ischemia/reperfusion injury in mice. Ferenbach DA, Sheldrake TA, Dhaliwal K, Kipari TM, Marson LP, Kluth DC, Hughes J. Kidney Int. 2012 Oct;82(8):928-33.

Imaging inflammation: Molecular strategies to visualize key components of the inflammatory cascade, from initiation to resolution. Dorward DA, Lucas CD, Rossi AG, Haslett C, Dhaliwal K. Pharmacol Ther. 2012 May 22.

Pulmonary and systemic effects of mononuclear leukopheresis. Barr L, Brittan M, Conway Morris A, Stewart A, Dhaliwal K, Anderson N, Turner M, Manson L, Simpson AJ. Vox Sang. 2012 Apr 12.

A novel subpopulation of monocyte-like cells in the human lung after LPS inhalation. Brittan M, Barr L, Conway Morris A, Duffin R, Rossi F, Johnston S, Monro G, Anderson N, Rossi AG, McAuley DF, Haslett C, Hirani N, Dhaliwal K, Simpson AJ. Eur Resp Journal, 2012. Jul:40(1):206-14.

Far red and NIR dye-peptoid conjugates for efficient immune cell labelling and tracking in preclinical models. Dhaliwal, K., Escher, G., Unciti-Broceta, A., McDonald, N., Simpson, A. J., Haslett, C. & Bradley, M. Nov-2011. Med chem comm. 2, 11, p. 1050-1053.

Cyclophilin A is a damage-associated molecular pattern molecule that mediates acetaminophen-induced liver injury. Dear JW, Simpson KJ, Nicolai MP, Catterson JH, Street J, Huizinga T, Craig DG, Dhaliwal K, Webb S, Bateman DN, Webb DJ. J Immunol. 2011 Sep 15;187(6):3347-52.

Screening of a combinatorial homing peptide library for selective cellular delivery. Svensen N, Díaz-Mochón JJ, Dhaliwal K, Planonth S, Dewar M, Armstrong JD, Bradley M. Angew Chem Int Ed Engl. 2011 Jun 27;50(27):6133-6.

Safe and efficient in vitro and in vivo gene delivery: tripodal cationic lipids with programmed biodegradability. Unciti-Broceta, A., Moggio, L., Dhaliwal, K., Pidgeon, L., Finlayson, K., Haslett, C. & Bradley, M. 2011. Journal of Materials Chemistry. 21, 7, p. 2154-2158.

Ly6Chi monocytes direct alternatively activated profibrotic macrophage regulation of lung fibrosis. Gibbons MA, MacKinnon AC, Ramachandran P, Dhaliwal K, Duffin R, Phythian-Adams AT, van Rooijen N, Haslett C, Howie SE, Simpson AJ, Hirani N, Gauldie J, Iredale JP, Sethi T, Forbes SJ. Am J Respir Crit Care Med. 2011 Sep 1;184(5):569-81.

Multi-modal molecular imaging approaches to detect primary cells in preclinical models. Dhaliwal K, Alexander L, Escher G, Unciti-Broceta A, Jansen M, Mcdonald N, Cardenas-Maestre JM, Sanchez-Martin R, Simpson J, Haslett C, Bradley M. Faraday Discuss. 2011;149:107-14; discussion 137-57.

C5a-mediated neutrophil dysfunction is RhoA-dependent and predicts infection in critically ill patients. Morris AC, Brittan M, Wilkinson TS, McAuley DF, Antonelli J, McCulloch C, Barr LC, McDonald NA, Dhaliwal K, Jones RO, Mackellar A, Haslett C, Hay AW, Swann DG, Anderson N, Laurenson IF, Davidson DJ, Rossi AG, Walsh TS, Simpson AJ. Blood. 2011 May 12;117(19):5178-88. Epub 2011 Feb 3.

Diagnostic importance of pulmonary interleukin-1{beta} and interleukin-8 in ventilator-associated pneumonia. Thorax. 2010 Mar; 65(3):201-7. Conway Morris A, Kefala K, Wilkinson TS, Moncayo-Nieto OL, Dhaliwal K, Farrell L, Walsh TS, Mackenzie SJ, Swann DG, Andrews PJ, Anderson N, Govan JR, Laurenson IF, Reid H, Davidson DJ, Haslett C,Sallenave JM, Simpson AJ.

Pain in neonates during screening for retinopathy of prematurity using binocular indirect ophthalmoscopy and wide-field digital retinal imaging: a randomised comparison. Arch Dis Child Fetal Neonatal Ed. 2009 Oct 8 Dhaliwal CA, Wright E, McIntosh N, Dhaliwal K, Fleck BW.

C5a mediates peripheral blood neutrophil dysfunction in critically ill patients. Am J Respir Crit Care Med. 2009 Jul 1;180(1):19-28. Conway Morris A, Kefala K, Wilkinson TS, Dhaliwal K, Farrell L, Walsh T, Mackenzie SJ, Reid H, Davidson DJ, Haslett C, Rossi AG, Sallenave JM, Simpson AJ.

Trappin-2 promotes early clearance of Pseudomonas aeruginosa through CD14-dependent macrophage activation and neutrophil recruitment. Am J Pathol. 2009 Apr;174(4):1338-46. Wilkinson TS, Dhaliwal K, Hamilton TW, Lipka AF, Farrell L, Davidson DJ, Duffin R, Morris AC, Haslett C, Govan JR, Gregory CD, Sallenave JM, Simpson AJ.

Dunking doughnuts into cells--selective cellular translocation and in vivo analysis of polymeric micro-doughnuts. Chem Commun (Camb). 2008 Aug 14;(30):3507-9 Alexander L, Dhaliwal K, Simpson J, Bradley M.

Galectin-3 reduces the severity of pneumococcal pneumonia by augmenting neutrophil function. Am J Pathol. 2008 Feb;172(2):395-405 Farnworth SL, Henderson NC, Mackinnon AC, Atkinson KM, Wilkinson T, Dhaliwal K, Hayashi K, Simpson AJ, Rossi AG, Haslett C, Sethi T.

Acute lung injury

neutrophils

monocytes

peptoids

Developing novel therapeutic strategies for acute lung injury and infection-peripheral blood monocyte depletion and prophylactic antimicrobial therapy

Thesis or Dissertation

Doctoral

PhD Doctor of Philosophy