Understanding trauma as a system of psycho-social harm: Contributions from the Australian royal commission into child sex abuse.

This article examines how particular understandings of trauma as a systemic form of psychosocial harm framed the establishment of the Australian Royal Commission into Institutional Responses to Child Sexual Abuse, informed its successful investigatory process, and shaped its recommendations and outcomes. In so doing, the Royal Commission makes an important contribution to the field of trauma studies, which has been characterized by contested histories and is subject to continuing debate in clinical and academic research. For much of the twentieth century, trauma and its impacts have been typically articulated through a bio-medical discourse of individual harm and health outcomes.

The Australian Royal Commission into Institutional Responses to Child Sexual Abuse.

The Royal Commission into Institutional Responses to Child Sexual Abuse is the largest royal commission in Australia's history and one of the largest public inquiries into institutional child abuse internationally. With an investment from the Australian government of half a billion dollars, it examined how institutions with a responsibility for children, both historically and in the present, have responded to allegations of child sexual abuse. Announced in the wake of previous Australian and international inquiries, public scandals and lobbying by survivor groups, its establishment reflected increasing recognition of the often lifelong and intergenerational damage caused by childhood sexual abuse and a strong political commitment to improving child safety and wellbeing in Australia.

Impaired phagocytosis of apoptotic cells by macrophages in chronic granulomatous disease is reversed by IFN-γ in a nitric oxide-dependent manner.

Immunodeficiency in chronic granulomatous disease (CGD) is well characterized. Less understood are exaggerated sterile inflammation and autoimmunity associated with CGD. Impaired recognition and clearance of apoptotic cells resulting in their disintegration may contribute to CGD inflammation.

TNFalpha inhibits apoptotic cell clearance in the lung, exacerbating acute inflammation.

Efficient removal of apoptotic cells is essential for resolution of inflammation. Failure to clear dying cells can exacerbate lung injury and lead to persistent inflammation and autoimmunity. Here we show that TNFalpha blocks apoptotic cell clearance by alveolar macrophages and leads to proinflammatory responses in the lung.

Assessment of apoptotic cell phagocytosis by macrophages.

Cells undergo apoptosis during development, tissue homeostasis, and disease, and are rapidly cleared by both professional and nonprofessional phagocytes. In the whole animal, this process is remarkably efficient and usually goes unnoticed. It is estimated that 2 x 10(11) cells are cleared each day and it has been suggested that detection of apoptotic cells in tissues should lead one to at least question the presence of a local clearance defect.

Impaired apoptotic cell clearance in CGD due to altered macrophage programming is reversed by phosphatidylserine-dependent production of IL-4.

Chronic granulomatous disease (CGD) is characterized by overexuberant inflammation and autoimmunity that are attributed to deficient anti-inflammatory signaling. Although regulation of these processes is complex, phosphatidylserine (PS)-dependent recognition and removal of apoptotic cells (efferocytosis) by phagocytes are potently anti-inflammatory. Since macrophage phenotype also plays a beneficial role in resolution of inflammation, we hypothesized that impaired efferocytosis in CGD due to macrophage skewing contributes to enhanced inflammation.

Surfactant proteins A and D suppress alveolar macrophage phagocytosis via interaction with SIRP alpha.

Rationale: Efficient removal of apoptotic cells is essential for the resolution of acute pulmonary inflammation. Alveolar macrophages ingest apoptotic cells less avidly than other professional phagocytes at rest but overcome this defect during acute inflammation. Surfactant protein (SP)-A and SP-D are potent modulators of macrophage function and may suppress clearance of apoptotic cells through activation of the transmembrane receptor signal inhibitory regulatory protein alpha (SIRP alpha).

Impairment of apoptotic cell engulfment by pyocyanin, a toxic metabolite of Pseudomonas aeruginosa.

Rationale: Cystic fibrosis lung disease is characterized by accumulation of apoptotic neutrophils, indicating impaired clearance of dying cells. Pseudomonas aeruginosa, the principal microbial pathogen in cystic fibrosis, manipulates apoptosis induction via production of toxic metabolites. Whether these metabolites, particularly pyocyanin, can also modulate apoptotic cell engulfment is unknown.

TNF-alpha inhibits macrophage clearance of apoptotic cells via cytosolic phospholipase A2 and oxidant-dependent mechanisms.

Removal of apoptotic cells from inflammatory sites is an important step in the resolution of inflammation. Both murine and human macrophages stimulated with TNF-alpha or directly administered arachidonic acid showed an impaired ability to ingest apoptotic cells (efferocytosis). The inhibition was shown to be due to generation of reactive oxygen species, was blocked with a superoxide dismutase mimetic, MnTBAP, and was mimicked by direct addition of H2O2.

Lovastatin enhances clearance of apoptotic cells (efferocytosis) with implications for chronic obstructive pulmonary disease.

Statins are potent, cholesterol-lowering agents with newly appreciated, broad anti-inflammatory properties, largely based upon their ability to block the prenylation of Rho GTPases, including RhoA. Because phagocytosis of apoptotic cells (efferocytosis) is a pivotal regulator of inflammation, which is inhibited by RhoA, we sought to determine whether statins enhanced efferocytosis. The effect of lovastatin on efferocytosis was investigated in primary human macrophages, in the murine lung, and in human alveolar macrophages taken from patients with chronic obstructive pulmonary disease.

Cell-surface calreticulin initiates clearance of viable or apoptotic cells through trans-activation of LRP on the phagocyte.

Apoptotic-cell removal is critical for development, tissue homeostasis, and resolution of inflammation. Although many candidate systems exist, only phosphatidylserine has been identified as a general recognition ligand on apoptotic cells. We demonstrate here that calreticulin acts as a second general recognition ligand by binding and activating LDL-receptor-related protein (LRP) on the engulfing cell.