**8. Alpha 1 AT**

eus. These organisms are difficult to eradicate in the CF patient, even with continuous prophylactic antibiotic treatment. Colonization is a doorway for infection, and CF is marked by periods of infection and significant decline in lung function known as exacerbations. The etiology of CF exacerbations is closely linked to fluctuations in the balance of bacterial flora

(5) Airway obstruction, colonization and episodic exacerbations promote a state of chronic inflammation in CF. In fact, the clinical status of the CF patient, especially during an exacer‐ bation, is tied more closely to the inflammatory response than the quantity and types of or‐ ganisms responsible for the infection. That inflammatory response is dominated by neutrophils (PMNs) and is responsible for the bulk of tissue damage in the CF airways. Bronchoalveolar lavage and sputum specimens from patients during exacerbation reveal high concentrations of both PMNs and their effectors and signaling molecules, such as neu‐ trophil elastase and IL-8, respectively. [56] IL-8 is a powerful recruiter of PMNs, and excess levels of this signaling molecule likely explains the PMN dominated inflammation in CF. Excess PMN recruitment to the lungs results in the discharge of their destructive weapons (described above) and subsequent killing of pathogens, apoptosis and damage to lung and airway tissue. More often the extreme inflammatory state leads to an aggregation of dying PMNs that result in dysregulated cell lysis, or necrosis, instead of a controlled destruction that mitigates tissue damage. When PMNs undergo necrosis instead of apoptosis they re‐ lease all of the activated enzymes and molecules designed to destroy pathogen into the in‐ terstitial space, further damaging an already taxed pulmonary environment. This damage results in a collection of mucopurulent debris that further clogs airways and provides a

The accepted method for diagnosing CF is by quantitative analysis of the chloride ion con‐ tent of the sweat. This is based on the premise that the CFTR protein is expressed in sweat glands as well, leading to excessive chloride ion concentration in the sweat. DNA immunor‐ eactive trypsinogen screening techniques are available that detect the presence of many of the common CF mutations. [52],[58] Although not standard, newer diagnostic and screening techniques include genotyping and measurement of the nasal potential difference. No mat‐ ter what the sweat chloride results, diagnosis of CF remains incomplete without molecular analysis of CFTR gene. Identification of the mutations, and confirmation of their trans state is necessary to provide the patient with an accurate prognosis and clear counseling to pa‐ rents as to their future reproductive options. Nasal potential difference assesses ion conduc‐ tance in vivo by observing changes in the voltage potential difference across the nasal

Advancements in therapeutics in CF in recent decades are the foundation for the prolonged survival of individuals noted above. Unfortunately, almost all current therapies the clinician has at his or her disposal only address the symptoms of CF without correcting the underly‐

in the airway. [55]

breeding ground for further infection. [57]

108 Oncogenesis, Inflammatory and Parasitic Tropical Diseases of the Lung

**7.6. Current cystic fibrosis therapeutics**

**7.5. Diagnosis of cystic fibrosis**

epithelium. [59]

#### **8.1. Overview/epidemiology**

α1-Antitrypsin (A1AT) deficiency (A1AD) is a form of COPD that is an extreme form of the condition, with the potential to develop COPD without excessive smoking. Patients with A1AT deficiency comprise approximately 5% of the global COPD population and have a predicted life span more than 10 years less than those of a life-long smoke with COPD. A1AT is believed by many to be an underreported condition affecting up to 1:2000 people. [63] Although this may seem extremely prevalent, those with the condi‐ tion only begin to appear symptomatic with cigarette smoking. The underreporting of A1AD may also be due to clinicians giving a diagnosis of idiopathic COPD, or COPD without a known underlying cause. [64]

#### **8.2. Etiology**

A1AD is a genetic disorder inherited in an autosomal recessive manner. Patients with A1AT have at least two mutations in a *trans* configuration in the A1AT gene. A1AD patients most often become symptomatic after cigarette smoking, although it is possible to present with emphysema in the third decade of life with no prior tobacco use. Patients present with wheezing, shortness of breath, rales, rhonci, and in some cases, liver failure. [65]

#### **8.3. Pathophysiology**

A1AT, an acute phase protein, is member of the serpin family of protease inhibitors. It is produced in the liver and serves to prevent activation and function of the neutrophil serine proteases HNE and proteinase-3. It is normally present at relatively high concentrations (1.5g/L) in the blood and is believed to play a prominent role in resolving inflammation un‐ der normal homeostasis. A1AD derived COPD is believed to be due to a protease/antipro‐ tease imbalance in which normal levels of HNE and proteinase-3 (P3) are uninhibited at sites of minor infection or inflammation. [66] The constitutively active HNE and P3 are left unencumbered to degrade extra-cellular matrix and begin a pro-inflammatory cascade of molecules that only further exacerbate the inflammation. Cigarette smoking is so destructive to those with A1AD because cigarette smoke directly inactivates A1AT, wreaking even fur‐ ther havoc on an already taxed system. The pathophysiology of A1AD is similar to that of COPD and thus the underdiagnosis of this condition.

**9. Neutrophilic/steroid resistant asthma**

cantly more common among females than males.

portant in the etiology of asthma. [72],[73]

response that is a hallmark of asthma.

Asthma was first defined in 1860 by Salter, a British clinician who ascertained that attacks were related to smooth muscle contraction. Asthma, at its core, is a chronic airway disease characterized by wheezing, coughing, and breathlessness with variable airway obstruction on pulmonary function testing. Asthma is a relatively common disease; recent reports by the Center for Disease Control (CDC) place its prevalence at approximately 12% (children) and 10% (adults) in the US. (www.cdc.gov) There appears to be a predominance of childhood asthma in non-Hispanic blacks, whereas non-Hispanic Whites, Hispanics, Asians, and Na‐ tive Americans all have similar frequencies of asthma. Additionally, the condition is signifi‐

New Frontiers in the Diagnosis and Treatment of Chronic Neutrophilic Lung Diseases

http://dx.doi.org/10.5772/53834

111

The development of asthma is thought to be associated with three major risk factors: genetic predisposition, and occupational and environmental factors. Although a precise list of genes associated with the atopic response in human has yet to be collated, GWAS studies in hu‐ man, and canines have revealed multiple loci related to the IgE response known to be im‐

Asthma begins in the airways with host contact of an allergen, following this, specific IGE antibodies are upregulated and initiate mast cell activation. Mast cell activation, in turn be‐ gins the early and late phase response. The early phase response is mediated by histamine, leukotriene C4, D4, and E4, and prostoglandin D2. After the early phase/hypersensitivity re‐ sponse, that late phase response begins. Eosinophils, basophils, neutrophils, and T cells are all recruited to the airway and produce inflammatory cytokines that propogate the allergic

Asthma is typically thought of as an eosinophilic disease, yet there have been numerous studies reporting an increase in neutrophil number and activation in sputum collected from steroid-resistant asthma patients. There are reports of up to 50% of asthma cases that have an increase in IL-8 and neutrophil burden, separate from eosinophilic inflammation. [74], [75] Because of the variability seen in primary immune cell burden in asthma neutrophilic asthma has recently begun to be viewed as a specific sub-type of the condition. [76] Patients with neutrophilic asthma have a more severe progression of disease, respond poorly to ther‐ apy, and are burdened with much high health care costs than typical asthma patients. Un‐ fortunately, there is little, if any, established dogma regarding neutrophilic asthma. Studies have only been able to describe correlative relationships between neutrophil burden and the phenotypic profile observed in neutrophilic asthma patients. [77] There has been extensive

**9.4. Role of neutrophils in neutrophilic and steroid-resistant asthma**

**9.1. Overview/epidemiology**

**9.2. Etiology**

**9.3. Pathophysiology**
