Title page
Contents
Foreword 3
Abstract 5
Background 7
AOP Development Strategy 9
Graphical representation 10
Summary of the AOP 11
Events 11
Key Event Relationships 11
Prototypical Stressors 12
Overall Assessment of the AOP 14
Appendix 1 - MIE, KEs and AO 39
List of MIEs in this AOP 39
Event: 1495: Substance interaction with the lung resident cell membrane components 39
List of Key Events in the AOP 47
Event: 1496: Increased, secretion of proinflammatory mediators 47
Event: 1497: Increased, recruitment of inflammatory cells 52
Event: 1498: Loss of alveolar capillary membrane integrity 56
Event: 1499: Increased, activation of T (T) helper (h) type 2 cells 62
Event: 1500: Increased, fibroblast proliferation and myofibroblast differentiation 65
Event: 68: Accumulation, Collagen 70
List of Adverse Outcomes in this AOP 74
Event: 1458: Pulmonary fibrosis 74
Appendix 2 - Key Event Relationships 79
List of Key Event Relationships in the AOP 79
List of Adjacent Key Event Relationships 79
Relationship: 1702: Interaction with the lung cell membrane leads to Increased proinflammatory mediators 79
Relationship: 1703: Increased proinflammatory mediators leads to Recruitment of inflammatory cells 89
Relationship: 1704: Recruitment of inflammatory cells leads to Loss of alveolar capillary membrane integrity 111
Relationship: 1705: Loss of alveolar capillary membrane integrity leads to Activation of Th2 cells 124
Relationship: 1706: Activation of Th2 cells leads to Increased cellular proliferation and differentiation 132
Relationship: 2652: Increased cellular proliferation and differentiation leads to Accumulation, Collagen 143
Relationship: 1629: Accumulation, Collagen leads to Pulmonary fibrosis 155
Relationship: 1702: Interaction with the lung cell membrane leads to Increased proinflammatory mediators 81
Table 1. Studies providing empirical evidence for the relationship between MIE (Event 1495) and KE1 (Event 1496). +: Severity of Response.... 81
Table 2. Time-scale related studies relevant to the MIE (Event 1495) - KE1 (Event1496) relationship 85
Relationship: 1703: Increased proinflammatory mediators leads to Recruitment of inflammatory cells 91
Table 1. Studies providing empirical evidence for the relationship between KE1 (Event 1496) and KE2 (Event 1497). +: Severity of Response.... 91
Relationship: 1704: Recruitment of inflammatory cells leads to Loss of alveolar capillary membrane integrity 113
Table 1. Studies providing empirical evidence for the relationship between KE2 (Event 1497) and KE3 (Event 1498). +: Severity of Response.... 113
Relationship: 1705: Loss of alveolar capillary membrane integrity leads to Activation of Th2 cells 125
Table 1. Studies providing empirical evidence for the relationship between KE3 (Event 1498) and KE4 (Event 1499). +: Severity of Response.... 125
Relationship: 1706: Activation of Th2 cells leads to Increased cellular proliferation and differentiation 134
Table 1. Studies providing empirical evidence for the relationship between KE4 (Event 1499) and KE5 (Event 1500). +: Severity of Response.... 134
Relationship: 2652: Increased cellular proliferation and differentiation leads to Accumulation, Collagen 144
Table 1. Studies providing empirical evidence for the relationship between KE5 (Event 1500) and KE6 (Event 68). +: Severity of Response.... 144