Host defence in the lung 1 Flashcards
Acute inflammation
- Vasodilation leads to exudation of plasma, including antibodies
- Activation of biochemical cascades, e.g. complement and coagulation cascades
- Migration of blood leukocytes into the tissues, mainly neutrophils but also some monocytes
- Initiated in the tissues, by epithelial production of hydrogen peroxide and release of cellular contents
- Amplified by specialist macrophages including: Kupffer cells (liver), alveolar macrophages (lung), histiocytes (skin, bone), dendritic cells
- Responding to pathogens or to tissue injury by recognising: PAMPs (pathogen-associated molecular patterns) DAMPs (damage-associated molecular patterns)
inflammation (double-edged sword)
defence against infection and a hostile environment BUT many of us will die of diseases caused by inflammatory processes
community acquired pneumonia
- Affects 250,000 adults per annum in UK
- 33% of these admitted to hospital
- Mortality of those admitted is around 10%
inflammation-mediated tissue damage in the lung
- Chronic obstructive pulmonary disease
- Acute respiratory distress syndrome
- Bronchiectasis
- Interstitial lung disease
- Asthma
ARDS
- Respiratory failure
- Water and neutrophils fill the alveoli
- Multi-system failure
- Any condition causing inadequate tissue oxygenation may precipitate ARDS, commonly trauma, lung infection, sepsis, surgery
pathophysiology of ARDS
- Endothelial leak – leading to extravasation of protein and fluid
- Lungs – reduced compliance, increased shunting
- Heart – pulmonary hypertension, reduced cardiac output
- Hypoxia
PRRs
used to recognise pathogens we have never seen before Signalling • Toll-like receptors (TLRs) • Nod-like receptors (NLRs) Endocytic • Mannose receptors • Glucan receptors • Scavenger receptors
toll-like receptors
- Funny flies, vulnerable to fungal infections
- Mice resistant to endotoxic shock
- Recognise conserved molecular patterns in pathogens
- TLR4 recognises lipopolysaccharide (LPS)
- TLR2 recognises lipotechoic acid (LTA)
- Also recognise endogenous mediators of inflammation
the alveolar macrophages
- AM comprise 93% of pulmonary macrophages
- Functionally, cytochemically and morphologically similar to mature tissue macrophages
- Long-lived and arise from monocytes
- Multiple different phenotypes of macrophage
the neutrophil
- 70% of all white blood cells
- 80 million are made each minute, more in sepsis
- Turnover 100 million a day
- Myeloid cells, related to monocytes and macrophages
- Contain granules (primary – myeloperoxidase, elastase, cathepsins, defensins secondary: receptors, lysozyme, collagenase)
neutrophil functions
- Identify the threat – receptors
- Activation
- Adhesion
- Migration/chemotaxis
- Phagocytosis
- Bacterial killing
neutrophil functions - receptors
Bacterial structures – cell walls, lipids, peptides
Host mediators – cytokines, complement, lipids
Host opsonins – FcR (immunoglobulin) CR3 (complement)
Host adhesion molecules
neutrophil functions - activation
Stimulus-response coupling
Signal transduction pathways involving calcium, protein kinases, phospholipases, G proteins
neutrophil functions - adhesion
Margination – selectins
Adhesion – integrins
Require changes in endothelium and in neutrophil
CD18 (beta-2 integrin) deficiency
- No transendothelial migration
- Delayed separation of umbilical cord
- Recurrent severe cutaneous and deep infections
